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When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations.

Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common methodology from physics used to describe rate-defining processes either in series or parallel. Our approach has been challenged in three recent publications, two published in this journal, but notably what is lacking is that none evaluate experimental pharmacokinetic data. As reviewed here, manuscripts from our laboratory have evaluated published experimental data, demonstrating that the Kirchhoff's Laws approach explains (1) why all of the experimental perfused liver clearance data appear to fit the equation that was previously believed to be the well-stirred model, (2) why linear pharmacokinetic systemic bioavailability determinations can be greater than 1, (3) why renal clearance can be a function of drug input processes, and (4) why statistically different bioavailability measures may be found for urinary excretion versus systemic concentration measurements. Our most recent paper demonstrates (5) how the universally accepted steady-state clearance approach used by the field for the past 50 years leads to unrealistic outcomes concerning the relationship between liver-to-blood Kpuu and hepatic availability FH , highlighting the potential for errors in pharmacokinetic evaluations based on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, those that were previously adequately explained with present pharmacokinetic theory, and those that were not. The publications that have attempted to rebut our position do not address unexplained experimental data, and we show here why their analyses are not valid. SIGNIFICANCE STATEMENT: The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes published pharmacokinetic data that has previously been unexplained. Three recent publications claim to refute our proposed methodology; these publications only make theoretical arguments, do not evaluate experimental data, and never demonstrate that the Kirchhoff methodology provides incorrect interpretations of experimental pharmacokinetic data, including statistically significant data not explained by present pharmacokinetic theory. We demonstrate why these analyses are invalid.

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios [RER = carbon dioxide production (V̇co2)/oxygen consumption (V̇o2)] during a 2-h 75-g oral glucose tolerance test (OGTT). After an 12-h overnight fast, 28 participants, 15 young (21-35 yr; 7 men and 8 women) and 13 older (60-80 yr; 7 men and 6 women), received venous primed-continuous infusions of [6,6-2H]glucose and [3-13C]lactate with a [Formula: see text] bolus. After a 90-min metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 min post glucose consumption, peaked at 60 min, and remained elevated. As assessed by rates of appearance (Ra) and disposal (Rd) and metabolic clearance rate (MCR), glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population after the oral glucose challenge. Finally, there were no differences in 12-h fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population after a glucose challenge. Furthermore, those physiological deficits are not detected from changes in RER during an OGTT.NEW & NOTEWORTHY To determine metabolic flexibility in response to an OGTT, we studied healthy young and older men and women to determine glucose kinetics and changes in RER. Compared to young subjects, glucose kinetics were suppressed in older healthy individuals during an OGTT. Surprisingly, the age-related changes in glucose flux were not reflected in RER measurements; thus, RER measurements do not give a complete view of metabolic flexibility in healthy individuals.

Background: Despite the high progress that has been made in the field of cardiology, the left ventricular assist device (LVAD) can still cause complications (thrombosis/bleeding) in heart failure (HF) patients after implantation. Complications develop due to the incorrect dose of antithrombotic therapy, due to the influence of the non-physiological shear stress of the device, and also due to inherited genetic polymorphisms. Therefore, the aim of our study is to identify the influence of the genetic polymorphisms on complication development in HF patients with implanted LVADs with prescribed antiplatelet therapy. Methods: Our study investigated 98 HF patients with/without complications who were genotyped for 21 single-nucleotide polymorphisms (SNPs) associated with cardiovascular events, the coagulation system, and the metabolism of warfarin and aspirin drugs. This study performed a more detailed analysis on genetic polymorphism in the UGT1A6 gene and its influence on aspirin dose. Results: SNP rs2070959 in the UGT1A6 gene showed a significant association with the group of HF patients with complications [(OR (95% CI): 4.40 (1.06–18.20), p = 0.044]. The genetic polymorphism of rs2070959 in the UGT1A6 gene showed a significant association in HF patients who received aspirin treatment on the 12th month after LVAD implantation [OR (95% CI): 5.10 (1.31–19.87), p = 0.018]. Moreover, our genotype distribution analysis showed that the GG genotype of rs2070959 in the UGT1A6 gene was significantly higher in the group with aspirin treatment than without treatment after the 12th month of treatment (50.0% vs. 0%, p = 0.008), especially in the group of patients with complications. A higher frequency of the GG genotype with long-lasting aspirin therapy up to the 12th month showed that 100 mg of aspirin was not an effective dose in the group of patients with complications. Conclusions: Our study identified that genotyping for genetic polymorphism rs2070959 in the UGT1A6 gene could predict the recommended dose of aspirin in HF patients, which could help to prevent and predict complication development after LVAD implantation. [ABSTRACT FROM AUTHOR]

Objective The present study investigated the impact of continuous infusion therapy with low-dose terlipressin (TP) combined with norepinephrine on hemodynamics, inflammatory markers, and prognosis in patients with severe septic shock. Materials and Methods Seventy-four patients with severe septic shock were randomly assigned to either a control group (n = 37) or an observation group (n = 37). Patients in the control group received norepinephrine alone, while those in the observation group received a continuous infusion of low-dose TP in addition to norepinephrine. To assess the effect of treatment, a set of clinical parameters was evaluated in both groups before and after treatment. These parameters included hemodynamic indicators (heart rate [HR], mean arterial pressure [MAP], central venous pressure [CVP], cardiac index [CI], and systemic vascular resistance index [SVRI]), levels of serum inflammatory markers (interleukin-8 [IL-8], tumor necrosis factor-α [TNF-α], and hypersensitivity C-reactive protein [hs-CRP]), renal function indicators (blood urea nitrogen [BUN], serum creatinine [SCr], and cystatin C [Cys-C]), serum procalcitonin (PCT), and lactate, as well as lactate clearance rate (LCR). Additionally, the acute physiology and chronic health evaluation II (APACHE II) score, 28-day mortality rate, multiple organ dysfunction syndrome (MODS) incidence rate, and adverse reaction incidence were also determined. Results Compared to baseline values, MAP, CVP, CI, SVRI, and LCR increased in both groups after treatment, while HR, levels of IL-8, TNF-α, hs-CRP, BUN, SCr, PCT, and lactate all decreased. Additionally, APACHE II scores also decreased. Furthermore, the observation group exhibited higher MAP, CVP, CI, SVRI, and LCR, along with lower HR, levels of IL-8, TNF-α, hs-CRP, BUN, SCr, PCT, and lactate than the control group after treatment. The observation group also had lower APACHE II score, 28-day mortality rate, MODS incidence rate, and adverse reaction incidence than the control group after treatment (P  < .05). Conclusion Continuous infusion therapy with low-dose TP combined with norepinephrine was effective in treating patients with severe septic shock, improving hemodynamic parameters, reducing the levels of inflammatory markers, promoting renal function recovery, and reducing the mortality rate. [ABSTRACT FROM AUTHOR]

Background: In uremic patients, the accumulation of gut-derived proteinbound uremic toxins (PBUTs) induces changes in the microenvironment of the patients, leading to changes in the elimination pattern of drugs. Aims: To assess ways in which PBUTs alter the CYP450 enzymes in hepatocytes as well as the possible effects of specific PBUTs on the metabolism and excretion of atorvastatin (ATV). Study Design: An experimental study. Methods: The experimental group was treated with long-term MHD for > 3 months, estimated-glomerular filtration rate (e-GFR) < 15 ml/ min, normal Alb level (35.0-55.0 g/l), and no urine; the control group was not treated with hemodialysis, e-GFR < 60 ml/min, normal Alb level, and normal urinary excretion function. A suitable UPLC-MS/MS method was developed for detecting the concentration of 4-hydroxy ATV. Fresh primary hepatocytes were isolated from rats, and the uptake of ATV was tested in the uremic serum (US) group, IS group, and HA group and compared with that in the normal serum group. The metabolic status of ATV in the US group, IS group, and HA group was compared with that in the ATV group. RLM were extracted, and the metabolic experiment of ATV was performed in a human CYP3A4 model. The influence of UTs on pregnane X receptor (PXR)/nuclear factor kappa B (NF-B) mRNA and the protein expression was also detected. Results: IS and HA inhibited the ATV metabolism to varying degrees, wherein IS was the most potent inhibitor, producing > 50% inhibition. Meanwhile, the protein expression of CYP3A4 was downregulated after incubation with US, IS, and HA (p < 0.01). The excretion of ATV was also inhibited by 59.24% and 71.95% after incubation with IS and HA, respectively. The effects of uremic toxins on PXR/NF-B mRNA and protein expression elucidated that PBUTs can inhibit ATV uptake and metabolism by exerting inhibitory effects on CYP3A4 through the PXR/ NF-B signaling pathway. Conclusion: ATV metabolism could be significantly altered in the presence of uremic toxins, suggesting a downregulated effect on the ATV uptake, possibly through Oatp1b1, and also on the activity of CYP3A4 through the PXR/NF-B signaling pathway. [ABSTRACT FROM AUTHOR]

It is not completely clear which organs are responsible for glucagon elimination in humans, and disturbances in the elimination of glucagon could contribute to the hyperglucagonemia observed in chronic liver disease and chronic kidney disease (CKD). Here, we evaluated kinetics and metabolic effects of exogenous glucagon in individuals with stage 4 CKD (n = 16), individuals with Child-Pugh A–C cirrhosis (n = 16), and matched control individuals (n = 16), before, during, and after a 60-min glucagon infusion (4 ng/kg/min). Individuals with CKD exhibited a significantly lower mean metabolic clearance rate of glucagon (14.0 [95% CI 12.2;15.7] mL/kg/min) compared with both individuals with cirrhosis (19.7 [18.1;21.3] mL/kg/min, P < 0.001) and control individuals (20.4 [18.1;22.7] mL/kg/min, P < 0.001). Glucagon half-life was significantly prolonged in the CKD group (7.5 [6.9;8.2] min) compared with individuals with cirrhosis (5.7 [5.2;6.3] min, P = 0.002) and control individuals (5.7 [5.2;6.3] min, P < 0.001). No difference in the effects of exogenous glucagon on plasma glucose, amino acids, or triglycerides was observed between groups. In conclusion, CKD, but not liver cirrhosis, leads to a significant reduction in glucagon clearance, supporting the kidneys as a primary site for human glucagon elimination. Article Highlights: This study was undertaken to gain insights into the elimination of glucagon in humans, as this is an important, yet not fully uncovered, part of glucagon physiology. We investigated whether individuals with chronic kidney disease or liver cirrhosis were characterized by an altered elimination of glucagon. We found that individuals with stage 4 chronic kidney disease exhibit a significantly reduced elimination of glucagon, while patients with liver cirrhosis have a preserved glucagon elimination. Our findings support the kidneys as the prevailing site of glucagon elimination in humans and shed light on glucagon-related pathophysiology in liver and kidney diseases. [ABSTRACT FROM AUTHOR]

Insulin is a key regulator of amino acid metabolism. Many plasma amino acids, including lysine and its metabolite, α-aminoadipic acid (α-AA), a predictor for developing diabetes, are elevated in insulin resistance (IR). In 18 overweight women with IR and polycystic ovary syndrome compared with 12 lean control women, high physiological insulin during a euglycemic clamp failed to normalize many elevated amino acid metabolites, including branched-chain and aromatic amino acids, α-aminobutyric acid, and lysine, but normalized α-AA. To understand the underpinnings of differential responses of lysine and its metabolic product α-AA to high physiological insulin in IR compared with control participants, we developed a kinetic model using [α-15N1]-lysine and [13C1]-α-AA as tracers and measured the two tracers simultaneously in α-AA by innovative mass spectrometry. High insulin increased lysine conversion to α-AA in the IR and control groups but failed to normalize plasma lysine concentrations in IR due to a decrease in lysine metabolic clearance rate (MCR). In contrast, despite higher conversion rates of lysine to α-AA by high insulin, α-AA concentration decreased in IR because of the sustained greater MCR of α-AA. The abnormal amino acids and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR. Article Highlights: This study aimed to determine whether high physiological insulin normalizes abnormal plasma amino metabolites in individuals with insulin resistance. High insulin levels failed to normalize many amino acids, including lysine, but normalized the lysine metabolite α-aminoadipic acid (α-AA) reported to predict future diabetes. A novel kinetic model was developed using two stable isotope tracers to measure lysine and α-AA kinetics simultaneously in humans during a single protocol using innovative mass spectrometry that can be applied to study other amino acid kinetics. High physiological insulin normalized α-AA in insulin resistance by maintaining its higher metabolic clearance, suggesting that high α-AA resulted from insulin resistance. [ABSTRACT FROM AUTHOR]

Ginsenoside Rb1 exhibits a wide range of biological activities, and gut microbiota is considered the main metabolic site for Rb1. However, the impact of gut microbiota on the pharmacokinetics of Rb1 are still uncertain. In this study, we investigated the gut microbiome changes and the pharmacokinetics after a 30 d Rb1 intervention. Results reveal that the systemic exposure and metabolic clearance rate of Rb1 and Rd were substantially affected after orally supplementing Rb1 (60 mg/kg) to rats. Significant increase in the relative abundance of Bacteroides cellulosilyticus in gut microbiota and specific glycoside hydrolase (GH) families, such as GH2, GH92, and GH20 were observed based on microbiome and metagenomic analysis. Moreover, a robust association was identified between the pharmacokinetic parameters of Rb1 and the relative abundance of specific Bacteroides species, and glycoside hydrolase families. Our study demonstrates that Rb1 administration significantly affects the gut microbiome, revealing a complex relationship between B. cellulosilyticus, key GH families, and Rb1 pharmacokinetics. [ABSTRACT FROM AUTHOR]

The development of safe and effective medications requires a profound understanding of their pharmacokinetic (PK) and pharmacodynamic properties. PK studies have been built through investigation of enzymes and transporters that drive drug absorption, distribution, metabolism, and excretion (ADME). Like many other disciplines, the study of ADME gene products and their functions has been revolutionized through the invention and widespread adoption of recombinant DNA technologies. Recombinant DNA technologies use expression vectors such as plasmids to achieve heterologous expression of a desired transgene in a specified host organism. This has enabled the purification of recombinant ADME gene products for functional and structural characterization, allowing investigators to elucidate their roles in drug metabolism and disposition. This strategy has also been used to offer recombinant or bioengineered RNA (BioRNA) agents to investigate the posttranscriptional regulation of ADME genes. Conventional research with small noncoding RNAs such as microRNAs (miRNAs) and small interfering RNAs has been dependent on synthetic RNA analogs that are known to carry a range of chemical modifications expected to improve stability and PK properties. Indeed, a novel transfer RNA fused pre-miRNA carrier-based bioengineering platform technology has been established to offer consistent and high-yield production of unparalleled BioRNA molecules from Escherichia coli fermentation. These BioRNAs are produced and processed inside living cells to better recapitulate the properties of natural RNAs, representing superior research tools to investigate regulatory mechanisms behind ADME. SIGNIFICANCE STATEMENT: This review article summarizes recombinant DNA technologies that have been an incredible boon in the study of drug metabolism and PK, providing investigators with powerful tools to express nearly any ADME gene products for functional and structural studies. It further overviews novel recombinant RNA technologies and discusses the utilities of bioengineered RNA agents for the investigation of ADME gene regulation and general biomedical research.

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B‐type (BNP) and C‐type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR‐C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle‐controlled incremental infusions of ovine proOSTN (83–133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose‐dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR‐C in regulating plasma concentrations of NPs and associated cGMP‐mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis. What is the central question of this study?What role does osteocrin (OSTN) have in integrated cardiovascular, renal and neurohumoral function in normal health?What is the main finding and its importance?Osteocrin is structurally similar to natriuretic peptides (NPs) that play a crucial role in cardiovascular homeostasis and binds to the NP receptor‐C (NPR‐C). Stepped doses of OSTN raised plasma atrial NP, B‐type NP, C‐type NP and cGMP and reduced arterial and venous pressures. Collectively, these findings provide strong evidence that increased NP levels result from competitive displacement from NPR‐C, not from increased NP secretion, suggesting that OSTN might play a role in maintaining cardiovascular homeostasis. [ABSTRACT FROM AUTHOR]

This article discusses the potential differences in optimal doses of heart failure medications between women and men. It highlights the biological factors that may contribute to these differences, such as variations in body composition, drug absorption, metabolism, and elimination. The article presents findings from observational studies that suggest women may require lower doses than men to achieve significant clinical benefits, particularly for certain medications. However, it emphasizes the need for further research and the inclusion of sex-specific data on adverse effects to establish truly personalized and effective treatment guidelines for both women and men with heart failure. The article also addresses the existing disparities in the treatment of women with heart failure and calls for more representative inclusion of women in clinical trials. [Extracted from the article]

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios [RER = carbon dioxide production (V̇ co 2)/oxygen consumption (V̇ o 2)] during a 2-h 75-g oral glucose tolerance test (OGTT). After an 12-h overnight fast, 28 participants, 15 young (21–35 yr; 7 men and 8 women) and 13 older (60–80 yr; 7 men and 6 women), received venous primed-continuous infusions of [6,6-2H]glucose and [3-13C]lactate with a H 13 C O 3 − bolus. After a 90-min metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 min post glucose consumption, peaked at 60 min, and remained elevated. As assessed by rates of appearance (Ra) and disposal (Rd) and metabolic clearance rate (MCR), glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population after the oral glucose challenge. Finally, there were no differences in 12-h fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population after a glucose challenge. Furthermore, those physiological deficits are not detected from changes in RER during an OGTT. NEW & NOTEWORTHY: To determine metabolic flexibility in response to an OGTT, we studied healthy young and older men and women to determine glucose kinetics and changes in RER. Compared to young subjects, glucose kinetics were suppressed in older healthy individuals during an OGTT. Surprisingly, the age-related changes in glucose flux were not reflected in RER measurements; thus, RER measurements do not give a complete view of metabolic flexibility in healthy individuals. [ABSTRACT FROM AUTHOR]

Background: Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Methods: Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors. Results: BRAF mutations were detected in 27% of the patients, and the BRAF-mutated subgroup had inferior overall survival compared to wild-type cases (median 16 vs 36 months, respectively, p < 0.001). BRAF mutations were associated with RNF43/RSPO aberrations and low expression of negative Wnt regulators (ligand-dependent Wnt activation). Furthermore, BRAF mutations were associated with gene expression changes in transport solute carrier proteins (specifically SLC7A6) and drug metabolism enzymes (CES1 and CYP3A4) that could influence the efficacy of MMC and irinotecan, respectively. BRAF-mutated tumors additionally exhibited increased expression of members of the novel butyrophilin subfamily of immune checkpoint molecules (BTN1A1 and BTNL9). Conclusions: BRAF mutations were frequently detected and were associated with particularly poor survival in this cohort, possibly related to ligand-dependent Wnt activation and altered drug transport and metabolism that could confer resistance to MMC and irinotecan. Drugs that target ligand-dependent Wnt activation or the BTN immune checkpoints could represent two novel therapy approaches. [ABSTRACT FROM AUTHOR]

Background and objectives: Methotrexate is widely utilized in the chemotherapy of malignant tumors and autoimmune diseases in the pediatric population, but dosing can be challenging. Several population pharmacokinetic models were developed to characterize factors influencing variability and improve individualization of dosing regimens. However, significant covariates included varied across studies. The primary objective of this review was to summarize and discuss population pharmacokinetic models of methotrexate and covariates that influence pharmacokinetic variability in pediatric patients. Methods: Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed. Results: Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models. Conclusion: A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification. [ABSTRACT FROM AUTHOR]

OBJECTIVE To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. RESEARCH DESIGN AND METHODS Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m²) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity. RESULTS At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (-31.1 ± 1.6 and -91.5 ± 12.4 mg/dL) than with SAXA (-7.1 ± 2.1 and -53 ± 10.5 mg/dL) or DAPA (-17.0 ± 1.1 and -42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA +3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg · kg-1 · min-1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, β-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu. CONCLUSIONS SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved β-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance. [ABSTRACT FROM AUTHOR]

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇ o 2 L/min) treadmill exercise at HA (460 mmHg; P I O 2 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues. NEW & NOTEWORTHY: Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue. [ABSTRACT FROM AUTHOR]

Simple Summary: Poor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient's quality of life. The significant interindividual variability associated with poor adherence results in suboptimal drug exposure and consequently in unfavourable patient outcomes. By characterizing the pharmacokinetics of trametinib, this study aims to assess (i) the adequacy of recommended doses to achieve efficacy thresholds and (ii) the impact of non-adherence on drug exposure. The latter was assessed by simulating different scenarios of missing one or more doses per week to highlight the risk of treatment failure associated with poor adherence. These results promote interprofessional collaboration and patient partnership to address patients' needs in order to ensure adherence to trametinib and in fine therapeutic success. Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence. [ABSTRACT FROM AUTHOR]

Agonists targeting the receptors of incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute apotential barrier to their use, particularly at higher doses. Multiple studies reviewed inthis article document thediverse effects of these drugs onthe glucagon-likepeptide-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery. [ABSTRACT FROM AUTHOR]

In this study, a mixed porcine–human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research. [ABSTRACT FROM AUTHOR]

This study investigated the effects of EPO on hemoglobin (Hgb) and hematocrit (Hct), time trial (TT) performance, substrate oxidation, and skeletal muscle phenotype throughout 28 days of strenuous exercise. Eight males completed this longitudinal controlled exercise and feeding study using EPO (50 IU/kg body mass) 3×/week for 28 days. Hgb, Hct, and TT performance were assessed PRE and on Days 7, 14, 21, and 27 of EPO. Rested/fasted muscle obtained PRE and POST EPO were analyzed for gene expression, protein signaling, fiber type, and capillarization. Substrate oxidation and glucose turnover were assessed during 90‐min of treadmill load carriage (LC; 30% body mass; 55 ± 5% V̇O2peak) exercise using indirect calorimetry, and 6‐6‐[2H2]‐glucose PRE and POST. Hgb and Hct increased, and TT performance improved on Days 21 and 27 compared to PRE (p < 0.05). Energy expenditure, fat oxidation, and metabolic clearance rate during LC increased (p < 0.05) from PRE to POST. Myofiber type, protein markers of mitochondrial biogenesis, and capillarization were unchanged PRE to POST. Transcriptional regulation of mitochondrial activity and fat metabolism increased from PRE to POST (p < 0.05). These data indicate EPO administration during 28 days of strenuous exercise can enhance aerobic performance through improved oxygen carrying capacity, whole‐body and skeletal muscle fat metabolism. [ABSTRACT FROM AUTHOR]

Venetoclax, a highly potent BCL‐2 inhibitor, is indicated for treatment of some hematologic malignancies as monotherapy, and/or in combination with other agents. Venetoclax pharmacokinetics has been extensively characterized in patients and healthy participants. After oral dosing, the median time to reach maximum plasma concentration ranged from 5 to 8 h and harmonic mean half‐life ranged from 14 to 18 h. Food increases venetoclax bioavailability by 3–5‐fold and venetoclax should be administered with food to ensure adequate and consistent bioavailability. Venetoclax is eliminated via cytochrome P450 (CYP)3A metabolism, and a negligible amount of unchanged drug is excreted in urine. Strong CYP3A/P‐glycoprotein inhibitors increased venetoclax exposures (AUC) by 1.44‐ to 6.90‐fold while a significant decrease (71%) has been observed when dosed with strong CYP3 inducers. Venetoclax does not inhibit or induce CYP enzymes or transporters. Venetoclax pharmacokinetics is not appreciably altered by age, weight, sex, but the exposure is up to twofold higher in participants from Asian countries. Mild‐to‐severe renal impairment or end‐stage renal disease do not alter venetoclax exposures, and venetoclax is not cleared by dialysis. Although mild‐to‐moderate hepatic impairment does not affect venetoclax exposures, twofold higher exposure was observed in subjects with severe hepatic impairment. Venetoclax exposure is comparable across patients with different hematologic malignancies and healthy participants. Overall, venetoclax exposure is only affected by food and CYP3A modulators and is only higher in Asian subjects and subjects with severe hepatic impairment. Venetoclax exposure–response relationships are malignancy‐dependent and can be different between monotherapy and combination therapy. [ABSTRACT FROM AUTHOR]

Background: Serum iron, an essential component of hemoglobin (Hb) synthesis in vivo, is a crucial parameter for evaluating the body's iron storage and metabolism capacity. Iron deficiency leads to reduced Hb synthesis in red blood cells and smaller red blood cell volume, ultimately resulting in iron‐deficiency anemia. Although serum iron cannot independently evaluate iron storage or metabolism ability, it can reflect iron concentration in vivo and serve as a good predictor of iron‐deficiency anemia. Therefore, exploring the influence of different serum iron levels on anemia and diagnosing and treating iron deficiency in the early stages is of great significance for patients with lung cancer. Aim: This study aims to explore the related factors of cancer‐related anemia (CRA) in lung cancer and construct a nomogram prediction model to evaluate the risk of CRA in patients with different serum iron levels. Methods: A single‐center retrospective cohort study was conducted, including 1610 patients with lung cancer, of whom 1040 had CRA. The relationship between CRA and its influencing factors was analyzed using multiple linear regression models. Lung cancer patients were divided into two groups according to their serum iron levels: decreased serum iron and normal serum iron. Each group was randomly divided into a training cohort and a validation cohort at a ratio of 7:3. The influencing factors were screened by univariate and multivariate logistic regression analyses, and nomogram models were constructed. The area under the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the models. Results: CRA in lung cancer is mainly related to surgery, chemotherapy, Karnofsky Performance Status (KPS) score, serum iron, C‐reactive protein (CRP), albumin, and total cholesterol (p < 0.05). CRA in lung cancer patients with decreased serum iron is primarily associated with albumin, age, and cancer staging, while CRA in lung cancer patients with normal serum iron is mainly related to CRP, albumin, total cholesterol, and cancer staging. The area under the ROC curve of the training cohort and validation cohort for the prediction model of lung cancer patients with decreased serum iron was 0.758 and 0.760, respectively. Similarly, the area under the ROC curve of the training cohort and validation cohort for the prediction model of lung cancer patients with normal serum iron was 0.715 and 0.730, respectively. The calibration curves of both prediction models were around the ideal 45° line, suggesting good discrimination and calibration. DCA showed that the nomograms had good clinical utility. Conclusion: Both models have good reliability and validity and have significant clinical value. They can help doctors better assess the risk of developing CRA in lung cancer patients. CRP is a risk factor for CRA in lung cancer patients with normal serum iron but not in patients with decreased serum iron. Therefore, whether CRP and the inflammatory state represented by CRP will further aggravate the decrease in serum iron levels, thus contributing to anemia, warrants further study. [ABSTRACT FROM AUTHOR]

Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin–electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients. [ABSTRACT FROM AUTHOR]

Background: The use of two or more drugs carries the potential risk of drug–drug interactions (DDIs), which may result in adverse reactions. Some human immunodeficiency virus (HIV)‐infected patients who receive antiretroviral therapy (ART) may require general anesthesia with propofol (PRL) before undergoing surgical treatment. Both PRL and ART drugs may lead to neuronal dysfunction, which can be accompanied by energy metabolism disorders. Neurons take in glucose mainly through glucose transporter 3 (Glut3) which is specifically expressed on the cell membranes of neurons. However, to date, no study has examined whether the DDIs of PRL and ART drugs interfere with glucose metabolism and Glut3 expression in neurons. Methods: An in vitro model was constructed using the primary cultures of neurons. PRL and ART drugs (EFV, AZT, and 3TC), were added at different concentrations (low, medium, and high). The neurons were exposed to the drugs for 1, 4, 8, and 12 h. The optimal drug concentration and exposure time were selected. The cellular survival rate, glucose concentration, electrophysiology, and the expression of Glut3 were detected. Results: There were no significant changes in the cellular survival rates of the neurons that were exposed to both PRL and ART drugs at low concentrations for 1 h. However, the survival rates of the neurons decreased significantly as the drug concentrations and durations increased. The glucose concentration of the neurons that were exposed to both PRL and the ART drugs was significantly decreased. The glucose concentration of the neurons was not affected by any individual drug. The amplitude of the action potential and the expression of Glut3 were decreased in the neurons that were exposed to both PRL and ART drugs. Conclusions: The main adverse reactions induced by the DDIs between PRL and the ART drugs were decreased glucose metabolism and neuronal damage, which were caused by inhibiting the expression of Glut3. More importantly, we found that decreases in glucose metabolism predated neuronal damage. [ABSTRACT FROM AUTHOR]

This comprehensive review focuses on the dynamics of branched-chain amino acids (BCAAs) metabolism and its clinical implications in chronic liver disease, with emphasis on the emerging concept of muscle–liver crosstalk. BCAAs, indispensable for protein synthesis and metabolic pathways, undergo unique tissue-specific processing in skeletal muscle and liver. The liver, responsible for amino acid metabolism, plays a distinctive role in sensing BCAAs catabolism, influencing glucose regulation and contributing to the systemic metabolism of BCAAs. Within the context of chronic liver disease, compromised liver metabolism becomes evident through amino acid abnormalities, particularly in the decrease of the Fischer ratio (BCAAs/aromatic amino acids concentrations in plasma). This reduction becomes important in assessing the severity of liver dysfunction due to its associations with adverse outcomes, including increased mortality and complications related to the liver disease. BCAAs supplementation, as explored in this review, emerges as a promising avenue, displaying positive effects on skeletal muscle mass, strength, and overall nutritional status in cirrhosis management. Understanding this interplay offers insights into therapeutic strategies for chronic liver diseases, exploring the way for precision interventions in clinical practice. [ABSTRACT FROM AUTHOR]

Aims: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6‐mediated metabolism of risperidone in patients with known CYP2D6 genotypes. Methods: The study included therapeutic drug monitoring (TDM) data from CYP2D6‐genotyped patients treated with risperidone. Risperidone and 9‐hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full‐scan high‐resolution mass spectrometry files was applied for semi‐quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9‐hydroxyrisperidone‐to‐risperidone ratio. Results: A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9‐hydroxyrisperidone‐to‐risperidone ratio (ρ > 0.6, P <.0001). The strongest correlation was observed for the M444‐to‐solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72–0.77, P <.0001). Conclusion: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6‐mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6. [ABSTRACT FROM AUTHOR]

The genome-wide profiling of 5-hydroxymethylcytosines (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for various diseases. The purpose of this study was to investigate 5hmC signals in serum cfDNA and identify novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5hmC profiles in cfDNA reflect the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. Moreover, we sought to identify predictors that would better stratify outcomes for women with intermediate-sensitive HGSOC. Women diagnosed with HGSOC and known platinum sensitivity status were selected for this study. Nano-hmC-Seal was performed on cfDNA isolated from archived serum samples, and differential 5hmC features were identified using DESeq2 to establish a model predictive of chemoresistance. A multivariate model consisting of three features (preoperative CA-125, largest residual implant after surgery, 5hmC level of OSGEPL) , stratified samples from intermediate sensitive, chemo-naive women diagnosed with HGSOC into chemotherapy-resistant- and sensitive-like strata with a significant difference in overall survival (OS). Independent analysis of The Cancer Genome Atlas data further confirmed that high OSGEPL1 expression is a favorable prognostic factor for HGSOC. We have developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC modified gene, OSGEPL1 , that predicted response to platinum-based chemotherapy in intermediate-sensitive HGSOC. Our multivariate model applies to chemo-naïve samples regardless if the patint was treated with adjuvant or neoadjuvant chemotherapy. These results merit further investigation of the predictive capability of our model in larger cohorts. • Chemotherapy does not alter global 5hmC deposition patterns on genomic features. • Neoadjuvant-treated platinum resistant disease is enriched in pathways associated with cellular responses to stress. • Adjuvant-treated platinum resistant disease is enriched in pathways associated with drug- and metabolism pathways. • An adjuvant chemotherapy-specific model stratifies intermediate sensitive disease into resistant- and sensitive-like groups. [ABSTRACT FROM AUTHOR]

For a number of years, our laboratory has been investigating the underlying reasons for the published poor in vitro-in vivo extrapolation (IVIVE) predictability of human clearance both from a theoretical and from an experimental perspective. Here, we critically examine clearance concepts and commonly employed IVIVE approaches, concluding that there is no theoretical reason that IVIVE should work, just as it does not. Our analysis, however, has identified 10 misconceptions and/or poorly understood aspects of clearance that are listed in the Conclusion section of this manuscript. Chief among these are that all published human drug clearance values are arterial clearances-clearance calculated as organ blood flow multiplied by the extraction ratio is the arterial clearance of the organ of elimination (and not the published drug clearance value)-and that the well-stirred model equation taught in all pharmacokinetic courses that relates organ blood flow, fraction unbound in blood, and intrinsic clearance has no validity. We further list 10 conclusions relating to the IVIVE process. The primary IVIVE-related conclusions are that the intrinsic clearance value determined from an in vitro incubation is an arterial intrinsic clearance, there is no theoretical basis upon which an arterial intrinsic clearance can be related to a whole-body arterial clearance to accomplish IVIVE, there are no published data demonstrating that in vitro intrinsic metabolic clearance can predict in vivo organ clearance as IVIVE assumes, and the scientific basis for the hypothesized albumin-mediated hepatic uptake phenomenon is invalid. We further propose three IVIVE process recommendations.

Accurate prediction of in vivo hepatic clearance is an essential part of successful and efficient drug development; however, many investigators have recognized that there are significant limitations in the predictability of clearance with a tendency for underprediction for primarily metabolized drugs. Here, we examine the impact of adding serum or albumin into hepatocyte and microsomal incubations on the predictability of in vivo hepatic clearance. The addition of protein into hepatocyte incubations has been reported to improve the predictability for high clearance (extraction ratio) drugs and highly protein-bound drugs. Analyzing published data for 60 different drugs and 97 experimental comparisons (with 17 drugs being investigated from two to seven) we confirmed the marked underprediction of clearance. However, we could not validate any relevant improved predictability within twofold by the addition of serum to hepatocyte incubations or albumin to microsomal incubations. This was the case when investigating all measurements, or when subdividing analyses by extraction ratio, degree of protein binding, Biopharmaceutics Drug Disposition Classification System class, examining Extended Clearance Classification System class 1B drugs only, or drug charge. Manipulating characteristics of small data sets of like compounds and adding scaling factors can appear to yield good predictability, but the carryover of these methods to alternate drug classes and different laboratories is not evident. Improvement in predictability of poorly soluble compounds is greater than that for soluble compounds, but not to a meaningful extent. Overall, we cannot confirm that protein addition improves in vitro-in vivo extrapolation predictability to any clinically meaningful degree when considering all drugs and different subsets. SIGNIFICANCE STATEMENT: The addition of protein into microsomal or hepatocyte incubations has been widely proposed to improve hepatic clearance predictions. To date, studies examining this phenomenon have not included appropriate negative controls where predictability is achieved without protein addition and have been conducted with small data sets of similar compounds that don't apply to alternate drug classes. Here, an extensive analysis of published data for 60 drugs and 97 experimental comparisons couldn't validate any relevant clinically improved clearance predictability with protein addition.

Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05-1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under- (or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of hepatocytes within a liver. More work is needed on multiple fronts, including the study of an expanded variety of virtual compound properties. Nevertheless, the results support the feasibility of the approach and plan.

Liposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN-38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI-1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two-compartment model with first-order elimination, with SN-38 formed directly by a first-order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN-38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN-38 clearance. Model evaluation was satisfactory for both irinotecan and SN-38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN-38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN-38 concentrations. In summary, the PKs of total irinotecan and SN-38 after administration of liposomal irinotecan were well-described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.

Sea cucumber (Apostichopus japonicus) is one of the cultured species with the highest production value to a single species in China’s marine agricultural industry with high nutritional and medicinal value. Body color influences numerous biological functions in sea cucumbers, and it has become a key trait in selective breeding. It is found that a cultivation environment with strong light intensity leads to a lighter body color of A. japonicus compared to dark conditions. However, little research has been conducted on the molecular mechanisms regulating body color in different breeding environments. In this study, we used Illumina sequencing to examine gene expression patterns in green and purple A. japonicus exposed to different culture conditions. Overall, the genes in the body wall of purple individuals were more affected by the environment. We also identified pathways that were potentially influenced by the breeding environment, such as “Drug metabolism - cytochrome P450”, “Porphyrin and chlorophyll metabolism”, “Phosphatidylinositol signaling system”, “TGF-beta signaling”, and “mTOR signaling”. The aim of this study was to determine the light conditions and breeding environment that are more favorable to the requirements of body color in A. japonicus and apply them to the selection of high-quality breeds. The results obtained will support the breeding of A. japonicus with specific traits and the production of seedlings to promote the development of this maricultural industry. [ABSTRACT FROM AUTHOR]

Pain is prevalent in patients with cirrhosis. Due to potential alterations in drug metabolism, risk for adverse effects, and complications from cirrhosis, physicians are often faced with difficult choices when choosing appropriate analgesics in these patients. Overall, acetaminophen remains the preferred analgesic. Despite its potential for intrinsic liver toxicity, acetaminophen is safe when used at 2 g/d. In contrast, non-selective nonsteroidals should be avoided due to their multiple side effects, including worsening renal function, blunting diuretic response, and increasing risk of portal hypertensive and peptic ulcer bleeding. Celecoxib can be administered for short term (≤5 days) in patients with Child's A and Child's B cirrhosis (50% dose reduction). Opioids carry the risk of precipitating hepatic encephalopathy and should generally be avoided, when possible. If clinical situation demands their use, opioid use should be limited to short-acting agents for short duration. Gabapentin and pregabalin are generally safe. Duloxetine should be avoided in hepatic impairment. Topical diclofenac and lidocaine seem to be safe in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Objective: A major side effect of cervical excision for high‐grade cervical intraepithelial neoplasia (CIN) is premature birth. A non‐invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high‐grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high‐risk human papillomavirus (hr‐HPV), compared with surgical treatment and placebo. Methods: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr‐HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta‐analyses checklist. Results: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod‐treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03–8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59–33.27) for histological regression to ≤CIN 1. The hr‐HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62–23.77). Conclusions: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo. Synopsis: The histological regression rate is 55% for high‐grade CIN treated with imiquimod and significant side‐effects were observed. [ABSTRACT FROM AUTHOR]

Purpose: To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine covariates affecting MTX disposition. Methods: We compared MTX PK profiles among neonates, children, and adults by performing a systematic literature search for published population MTX models and conducted a Monte Carlo-based meta-analysis. Subsequently, we evaluated study quality and covariates significantly affecting dosage regimens and compared LDMTX and HDMTX PK profiles. Results: Of the total 40 studies included, 34 were HDMTX, and six were LDMTX studies. For HDMTX, three studies involving neonates reported estimated apparent clearances (median, range) of 0.53 (0.27–0.77) L/kg/h; for 14 studies involving children, 0.23 (0.07–0.23) L/kg/h; and for 13 involving adults, 0.11 (0.03–0.22) L/kg/h. Neonates had a higher volume of distribution than children and adults. For LDMTX studies, apparent clearance was 0.085 (0.05–1.68) L/kg/h, and volume of distribution was 0.25 (0.018–0.47) L/kg, lower than those of HDMTX studies, with large between-subject variability. Bodyweight significantly influenced apparent clearance and volume of distribution, whereas renal function mainly influenced clearance. Mutations in certain genes reduced MTX clearance by 8–35.3%, whereas those in others increased it by 15–48%. Body surface area (BSA) significantly influenced apparent clearance with a median reduction of 51% when BSA increased in pediatric patients. Conclusions: Methotrexate dosage regimens were primarily based on body surface area and renal function. Further studies are needed to evaluate MTX pharmacokinetics and pharmacodynamics in both children (especially infants) and adults. [ABSTRACT FROM AUTHOR]

Background: Therapeutic hypothermia (TH) is a widely practiced neuroprotective strategy for neonates with hypoxic-ischemic encephalopathy. Induced hypothermia is associated with shivering, cold pain, agitation, and distress. Objective: This scoping review determines the breadth of research undertaken for pain and stress management in neonates undergoing hypothermia therapy, the pharmacokinetics of analgesic and sedative medications during hypothermia and the effect of such medication on short- and long-term neurological outcomes. Methods: We searched the following online databases namely, (i) MEDLINE, (ii) Web of Science, (iii) Cochrane Library, (iv) Scopus, (v) CINAHL, and (vi) EMBASE to identify published original articles between January 2005 and December 2022. We included only English full-text articles on neonates treated with TH and reported the sedation/analgesia strategy used. We excluded articles that reported TH on transport or extracorporeal membrane oxygenation, did not report the intervention strategies for sedation/analgesia, and reported hypoxic-ischemic encephalopathy in which hypothermia was not applied. Results: The eligible publications (n = 97) included cohort studies (n = 72), non-randomized experimental studies (n = 2), pharmacokinetic studies (n = 4), dose escalation feasibility trial (n = 1), cross-sectional surveys (n = 5), and randomized control trials (n = 13). Neonatal Pain, Agitation, and Sedation Scale (NPASS) is the most frequently used pain assessment tool in this cohort. The most frequently used pharmacological agents are opioids (Morphine, Fentanyl), benzodiazepine (Midazolam) and Alpha2 agonists (Dexmedetomidine). The proportion of neonates receiving routine sedation-analgesia during TH is center-specific and varies from 40–100% worldwide. TH alters most drugs' metabolic rate and clearance, except for Midazolam. Dexmedetomidine has additional benefits of thermal tolerance, neuroprotection, faster recovery, and less likelihood of seizures. There is a wide inter-individual variability in serum drug levels due to the impact of temperature, end-organ dysfunction, postnatal age, and body weight on drug metabolism. Conclusions: No multidimensional pain scale has been tested for reliability and construct validity in hypothermic encephalopathic neonates. There is an increasing trend towards using routine sedation/analgesia during TH worldwide. Wide variability in the type of medication used, administration (bolus versus infusion), and dose ranges used emphasizes the urgent need for standardized practice recommendations and guidelines. There is insufficient data on the long-term neurological outcomes of exposure to these medications, adjusted for underlying brain injury and severity of encephalopathy. Future studies will need to develop framework tools to enable precise control of sedation/analgesia drug exposure customized to individual patient needs. [ABSTRACT FROM AUTHOR]

Introduction: Temperature monitoring intraoperatively is standard of care for almost all surgical cases and is necessary due to the important role that temperature plays in maintaining body homeostasis, anaesthetic drug metabolism, and recovery. However, invasive and user-unfriendly methods like measuring temperature in the oesophagus, tympanic membrane, or rectum have limitations. An alternative site for measuring core body temperature could be the nasopharynx, as its mucosa is supplied by branches of the internal carotid artery. Aim: To determine the accuracy of the nasopharyngeal probe in comparison to oesophageal temperature probe and to identify appropriate insertion depths for measuring core body temperature. Materials and Methods: Sixty patients scheduled for elective non-cardiac surgery under general anaesthesia lasting 60 minutes or more. A nasopharyngeal probe was inserted past the nares to a depth of 20 cm, and an oesophageal temperature probe was inserted to a depth of 40 cm past the incisors. The nasopharyngeal probe was gradually pulled out after induction, and temperatures at various depths were recorded at regular intervals. The observed depths of the nasopharyngeal probe that correlated with the oesophageal temperature were considered as the endpoints. Data was entered into Microsoft Excel and analysed using Statistical Package for Social Sciences (SPSS) version 25.0. Results: The study population consisted of 60 patients, with 31 males and 29 females, a mean age of 50 years, mean body mass index of 26 kg/m², American Society of Anaesthesiologists (ASA) (physical status) of 1 (n=27) and 2 (n=33). The insertion depths of 10 to 20 cm for the nasopharyngeal probe showed a mean temperature difference of ±0.3°C compared to the reference oesophageal temperature. This difference fell within the clinically acceptable accuracy range of 0 to 0.3°C (temperature mean difference ±1.96 SD) for both probes. Conclusion: The nasopharyngeal probe offers a minimally invasive method for measuring body temperature and is easily accessible for probe placement. However, the optimal depth of insertion past the nares has not been well established. Based on the results, which showed that the mean temperature difference between the two probes fell within the specified accuracy range when the nasopharyngeal probe was inserted to a depth range of 10 to 20 cm from the nares, it is advisable to use this depth range for core body temperature measurement in non cardiac surgeries. [ABSTRACT FROM AUTHOR]

About 10% of all home peritoneal dialysis regimens in children with chronic kidney disease stage 5 are reported to involve some form of a tidal peritoneal dialysis (TPD) prescription. Despite this, there remain several gaps in how pediatric nephrologists approach the use of TPD. This stems from a combination of factors such as the confusing technical terminology pertaining to TPD, seemingly conflicting data on the risks, benefits, and indications for TPD, and lastly, limited published guidelines on the practical aspects of how to write a TPD prescription, based on the indication, in children. Our educational review, using evidence-based data, attempts to bridge this gap and provide an easy-to-use guide on the key practical aspects of TPD in children. [ABSTRACT FROM AUTHOR]

CYP2C19 is a highly polymorphic gene responsible for the metabolism of commonly used drugs. CYP2C19*1, the wild-type allele, is associated with normal enzyme activity, whereas CYP2C19*2 and CYP2C19*17 lead to null and increased enzyme activity, respectively. The use of different instruments to perform the same pharmacogenetic tests should not affect the reliability of the results reported to clinicians, as required by the ISO 15189 standard. Genotyping assays allowed for the identification of gene variants corresponding to the CYP2C19*2 and CYP2C19*17 haplotypes in 44 selected samples. Each sample was analyzed in duplicate using the Thermo Fisher Taqman Drug Metabolism probes CYP2C19*2: c_25986767_70 (rs4244285) and CYP2C19*17: c_469857_10 (rs12248560). The experiments were performed on two widely used types of real-time PCR analyzers: ABI PRSIM™7500 and QuantStudioTM12KFlex (both from Applied Biosystems, Thermofisher). The data were analyzed in a Thermo Fisher Cloud facility. The analysis was performed independently by two qualified professionals. Both different instruments and analysts' interpretations were consistent in identifying the native homozygous, heterozygous, and mutant homozygous variants for CYP2C19*2 and CYP2C19*17. The results provided by both the primary and backup analyzers showed a perfect correlation. This would allow for the use of the backup analyzer in case the main one is not available. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a multifactorial disorder with contributions from hormones, genetics, and the environment, predominantly affecting young women. Cardiovascular disease is the primary cause of mortality in SLE, and hypertension is more prevalent among SLE patients. The dysregulation of both innate and adaptive immune cells in SLE, along with their infiltration into kidney and vascular tissues, is a pivotal factor contributing to the cardiovascular complications associated with SLE. The activation, proliferation, and differentiation of CD4+ T cells are intricately governed by cellular metabolism. Numerous metabolic inhibitors have been identified to target critical nodes in T cell metabolism. This review explores the existing evidence and knowledge gaps concerning whether the beneficial effects of metabolic modulators on autoimmunity, hypertension, endothelial dysfunction, and renal injury in lupus result from the restoration of a balanced immune system. The inhibition of glycolysis, mitochondrial metabolism, or mTORC1 has been found to improve endothelial dysfunction and prevent the development of hypertension in mouse models of SLE. Nevertheless, limited information is available regarding the potential vasculo-protective effects of drugs that act on immunometabolism in SLE patients. [ABSTRACT FROM AUTHOR]

Purpose: [13C]Bicarbonate formation from hyperpolarized [1‐13C]pyruvate via pyruvate dehydrogenase, a key regulatory enzyme, represents the cerebral oxidation of pyruvate and the integrity of mitochondrial function. The present study is to characterize the chronology of cerebral mitochondrial metabolism during secondary injury associated with acute traumatic brain injury (TBI) by longitudinally monitoring [13C]bicarbonate production from hyperpolarized [1‐13C]pyruvate in rodents. Methods: Male Wistar rats were randomly assigned to undergo a controlled‐cortical impact (CCI, n = 31) or sham surgery (n = 22). Seventeen of the CCI and 9 of the sham rats longitudinally underwent a 1H/13C‐integrated MR protocol that includes a bolus injection of hyperpolarized [1‐13C]pyruvate at 0 (2 h), 1, 2, 5, and 10 days post‐surgery. Separate CCI and sham rats were used for histological validation and enzyme assays. Results: In addition to elevated lactate, we observed significantly reduced bicarbonate production in the injured site. Unlike the immediate appearance of hyperintensity on T2‐weighted MRI, the contrast of bicarbonate signals between the injured region and the contralateral brain peaked at 24 h post‐injury, then fully recovered to the normal level at day 10. A subset of TBI rats demonstrated markedly increased bicarbonate in normal‐appearing contralateral brain regions post‐injury. Conclusion: This study demonstrates that aberrant mitochondrial metabolism occurring in acute TBI can be monitored by detecting [13C]bicarbonate production from hyperpolarized [1‐13C]pyruvate, suggesting that [13C]bicarbonate is a sensitive in‐vivo biomarker of the secondary injury processes. [ABSTRACT FROM AUTHOR]

What is known and objectiveTenofovir exposure is increased in non-pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy.MethodsData were collected through the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s protocol. This was a nonrandomized, open-label, parallel-group and multicentre phase-IV prospective study in pregnant women with HIV. Intensive steady-state 24-h pharmacokinetic profiles were collected during the third trimester of pregnancy and postpartum. Tenofovir was measured in plasma using validated liquid chromatography-mass spectrometry method (quantification limit: 10 ng/ml). Statistical tests compared paired and between group pharmacokinetic data.Results and discussionIn women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC0-24 was 27% lower (2.2 mcg·h/ml vs 2.8 mcg·h/ml, p = 0.002) and oral clearance was 27% higher (61 L/h vs 48 L/h, p = 0.001) during the third trimester compared to paired postpartum data. In women receiving lopinavir/ritonavir (n = 10), tenofovir AUC0-24 and oral clearance were not different antepartum compared to postpartum. Women with and women without concomitant lopinavir/ritonavir displayed no significant differences in postpartum tenofovir pharmacokinetics.What is new and conclusionTenofovir exposure during the third trimester was reduced compared to postpartum in pregnant women not receiving lopinavir/ritonavir, but not in pregnant women also receiving lopinavir/ritonavir. Our findings suggest that pregnancy confounds the expected decrease in tenofovir exposure with concomitant lopinavir/ritonavir in non-pregnant adults. These findings illustrate the need for drug-drug interaction studies in pregnant women as drug disposition differs significantly in pregnant women compared to non-pregnant adults.

Electronic nicotine delivery systems (ENDS) such as e-cigarettes and heated tobacco products are novel battery-operated devices that deliver nicotine without combustion of tobacco. Because cigarette smoking is sustained by nicotine addiction and the toxic combustion products are mainly responsible for the harmful effects of smoking, ENDS could be used to promote smoking cessation while exposing users to lower levels of toxicants compared with conventional cigarettes. The currently available evidence from clinical and observational studies indicates a potential role of e-cigarettes as smoking cessation aids, although many continue to use e-cigarettes long after quitting smoking. Nicotine and toxicant delivery vary considerably by device and depend on the characteristics of the e-liquid formulation. Because smokers tend to titrate their nicotine intake to maintain their desired pharmacologic effects, device and liquid characteristics need to be considered when using ENDS as an aid to quit smoking. Factors potentially limiting their use are the currently still unknown long-term safety of these products and concerns regarding widespread use among youth. Implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration are discussed.

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. There is only one valid definition of clearance. Defining organ clearance solely on the basis of systemic blood concentrations can lead to drug dosing errors when drug effect sites reside either in an eliminating organ exhibiting incremental clearance or in a non-eliminating organ where intraorgan concentration is governed by transporter actions. Attempts to predict clearance are presently hampered by the lack of recognition that what we are trying to predict is a well-stirred model clearance.