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Oral drug absorption involves drug permeation across the apical and basolateral membranes of enterocytes. Although transporters mediating the influx of anionic drugs in the apical membranes have been identified, transporters responsible for efflux in the basolateral membranes remain unclear. Monocarboxylate transporter 6 (MCT6/SLC16A5) has been reported to localize to the apical and basolateral membranes of human enterocytes and to transport organic anions such as bumetanide and nateglinide in the Xenopus oocyte expression system; however, its transport functions have not been elucidated in detail. In this study, we characterized the function of MCT6 expressed in HEK293T cells and explored fluorescent probes to more easily evaluate MCT6 function. The results illustrated that MCT6 interacts with CD147 to localize at the plasma membrane. When the uptake of various fluorescein derivatives was examined in NaCl-free uptake buffer (pH 5.5), the uptake of 5-carboxyfluorescein (5-CF) was significantly greater in MCT6 and CD147-expressing cells. MCT6-mediated 5-CF uptake was saturable with a K m of 1.07 mM and inhibited by several substrates/inhibitors of organic anion transporters and extracellular Cl ion with an IC 50 of 53.7 mM. These results suggest that MCT6 is a chloride-sensitive organic anion transporter that can be characterized using 5-CF as a fluorescent probe. [Display omitted] [ABSTRACT FROM AUTHOR]

Caco-2 cell monolayers are widely employed as an in vitro model of the intestinal barrier, capable of accurately predicting the absorption of conventional small-molecule drugs. However, this model may not be applicable to all drugs, and the accuracy of absorption prediction is typically poor for high molecular weight drugs. Recently, human induced pluripotent stem (iPS) cell-derived small intestinal epithelial cells (hiPSC-SIECs), exhibiting properties similar to those of the small intestine when compared with Caco-2 cells, have been developed and are considered a novel candidate model for in vitro evaluation of intestinal drug permeability. Therefore, we evaluated the utility of human hiPSC-SIECs as a new in vitro model to predict the intestinal absorption of middle-molecular weight drugs and peptide drugs. Firstly, we showed that the hiPSC-SIEC monolayer allowed faster transport of peptide drugs (insulin and glucagon-like peptide-1) than the Caco- 2 cell monolayer. Second, we revealed that hiPSC-SIECs require divalent cations (Mg2+ and Ca2+) to maintain barrier integrity. Third, we demonstrated that experimental conditions established for Caco-2 cells are not persistently applicable to hiPSC-SICEs when analyzing absorption enhancers. Comprehensively clarifying the features of hiPSC-SICEs is essential to establish a new in vitro evaluation model. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) may limit oral drug absorption of substrate drugs due to intestinal efflux. Therefore, regulatory agencies require investigation of new chemical entities as possible inhibitors of P-gp in vitro. Unfortunately, inter-laboratory and inter-assay variability have hindered the translatability of in vitro P-gp inhibition data to predict clinical drug interaction risk. The current study was designed to evaluate the impact of potential IC 50 discrepancies between two commonly utilized assays, i.e., bi-directional Madin-Darby Canine Kidney-MDR1 cell-based and MDR1 membrane vesicle-based assays. When comparing vesicle- to cell-based IC 50 values (n = 28 inhibitors), non-P-gp substrates presented good correlation between assay formats, whereas IC 50 s of P-gp substrates were similar or lower in the vesicle assays. The IC 50 s obtained with a cell line expressing relatively low P-gp aligned more closely to those obtained from the vesicle assay, but passive permeability of the inhibitors did not appear to influence the correlation of IC 50 s, suggesting that efflux activity reduces intracellular inhibitor concentrations. IC 50 s obtained between two independent laboratories using the same assay type showed good correlation. Using the G-value (i.e., ratio of estimated gut concentration-to-inhibition potency) >10 cutoff recommended by regulatory agencies resulted in minimal differences in predictive performance, suggesting this cutoff is appropriate for either assay format. [ABSTRACT FROM AUTHOR]

The study aimed to increase the intestinal solubility and absorption of orally bioavailable clopidogrel-bisulfate (CPB) by complexing with hydroxypropyl-β-cyclodextrin (HCD) to form a binary inclusion complex that was stabilized by Tween 80 (T80) resulting into mixed inclusion complex. The results of phase solubility studies and molecular docking of CPB with β-cyclodextrin (β-CD) and HCD suggested higher solubility and binding energy of the stable CPB: HCD complex in the presence of T80 as compared to the CPB: β-CD complex. The D-Optimal mixture design was used to optimize the formulation containing the CPB: HCD: T80 mixed inclusion complex. The results suggest the enhanced stability of the CPB: HCD inclusion complex in the presence of T80. The spectral attributes confirmed the inclusion complexation and pointed out the central position of CPB in a hydrophilic cavity of HCD. Further, the prepared soft gelatin capsule successfully confirmed the importance of obliterating the intestinal precipitation associated problem of CPB through an in-vitro release study. The anticoagulant a ctivity in rabbits confirmed that soft gelatin capsules showed 1.2 folds and 1.3 folds increase in clotting time, 1.2 fold and 1.5 folds increase in bleeding time when compared to marketed formulation and pure drug, respectively. Conclusively, soft gelatin capsules exhibit the potential to enhance the oral bioavailability of CPB, leading to reduction of the dose and dose-related side effects. [Display omitted] • CPB: HP-β-CD: T80 inclusion complex was successfully prepared using kneading method. • Molecular docking and spectral attributes confirmed inclusion complex formation. • CPB: HP-β-CD: T80 mixed inclusion complex showed chemical stability at alkaline pH. • Prepared soft gelatin capsule showed improved solubility and anticoagulant activity. [ABSTRACT FROM AUTHOR]

Weakly basic compounds propose biopharmaceutics risks due to the possibility of precipitation out of solution when passing from the stomach to the intestine. This behavior would limit the available drug for absorption and in turn reduces the plasma exposure at dose escalation scenarios in phase 1 clinical trials. In vitro precipitation studies along with computational models are often used to assess the risks of intestinal precipitation and provide insights about the parameters that should be controlled to minimize the risks of low absorption at high doses. In this work, both parameter sensitivity analysis and pH shift precipitation methods were used to guide the formulation approach and select excipients to reduce the risks associated with intestinal absorption of a weakly basic model compound. The simulations showed that absorption is sensitive to gastric pH and precipitation time which could be manipulated by formulation approaches. Other factors such as particle size and gastric residence time showed no impact. Precipitation studies using pH shift method were used to screen acidic excipients and polymers that will be added in a combination to boost supersaturation and retard precipitation. Hydroxy propyl methyl cellulose acetate succinate (HPMCAS) polymer middle grade was selected along with para-toluene sulfonic acid as the two excipients that would provide the highest supersaturation among the tested excipients. Merging both in vitro testing and computational models showed great merit in reducing time for selecting excipient for enabling formulation by focusing on the most influential formulation parameter for drug absorption. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the contributions of multiple transport mechanisms to the intestinal uptake of serotonin (5-HT) by employing a variety of in vitro experimental techniques, focusing on organic cation transporters expressed in the gastrointestinal (GI) tract, such as SERT, PMAT, THTR2, OCT3, and OCTN2. Analysis of the concentration dependence of 5-HT uptake by Caco-2 cells revealed multi-affinity kinetics with high-affinity and low-affinity components, suggesting that multiple transporters are involved in the intestinal 5-HT uptake. Comparative analysis of transporters using K m values obtained in Xenopus oocyte expression systems suggested that SERT is responsible for the high-affinity transport, while PMAT, THTR2, and OCT3 contribute to the low-affinity transport. Further analysis indicated that the relative contributions of SERT and PMAT to the intestinal 5-HT uptake (0.01 µM) are approximately 94.9% and 1.1%, respectively. Interestingly, at the concentration of 10 µM, the reported steady-state concentration of 5-HT in the human colon, the contributions of SERT, PMAT, THTR2, and OCT3 were estimated to be approximately 37.0%, 1.0%, 18.2%, and 20.5%, respectively. In conclusion, the present study indicated that the contributions of multiple transporters to 5-HT uptake in the GI tract are dependent upon the colon luminal concentration of 5-HT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Supersaturation and precipitation within the gastrointestinal tract can influence oral absorption of active pharmaceutical ingredients (APIs). Supersaturation of weakly basic APIs upon transfer from the stomach into the small intestine may enhance their absorption, while salt forms of poorly soluble weak acids may generate supersaturated solutions in both stomach and intestine. Likewise, APIs with solubility-limited absorption may be developed as enabling formulations intended to produce supersaturated solutions of the API in the gut. Integrating the supersaturation/precipitation characteristics of the API into the biopharmaceutical risk classification enables comprehensive mapping of potential developability risks and guides formulation selection towards optimizing oral bioavailability (BA). The refined Developability Classification System (rDCS) provides an approach for this purpose. In this work, the rDCS strategy is revisited and a stratified approach integrating the in vitro supersaturation and precipitation behavior of APIs and their formulations is proposed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The clinical applications of paclitaxel (PTX), a natural compound with broad-spectrum antitumor effects, have been markedly limited owing to its poor oral bioavailability and lack of targeting ability. Recently, several drug carriers, such as TPGS 2k , gelatin (Gel), cyclodextrin (CD), and hyaluronic acid (HA), have been identified as promising enhancers of drug efficacy. Therefore, Gel-grafted CD (GEL-CD) and HA-grafted CD (HA-CD) were synthesized via grafting, and PTX-loaded TPGS 2k /GEL-CD/HA-CD nanoparticles (TGHC-PTX-NPs) were successfully prepared using the ultrasonic crushing method. The mean particles size, polydispersity index, and Zeta potential of TGHC-PTX-NPs were 253.57 ± 2.64 nm, 0.13 ± 0.03, and 0.087 ± 0.005 mV, respectively. TGHC-PTX-NPs with an encapsulation efficiency of 61.77 ± 0.47% and a loading capacity of 6.86 ± 0.32% appeared round and uniformly dispersed based on transmission electron microscopy. In vitro release data revealed that TGHC-PTX-NPs had good sustained-release properties. Further, TGHC-PTX-NPs had increased the targeted uptake by HeLa cells as HA can specifically bind to the CD44 receptor at the cell surface, and its intestinal absorption is related to caveolin-mediated endocytosis. The pharmacokinetic results indicated that TGHC-PTX-NPs significantly enhanced the absorption of PTX in vivo compared to the PTX suspension, with a relative bioavailability of 227.21%. Such findings indicate the potential of TGHC-PTX-NPs for numerous clinical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the contributions of multiple transport mechanisms to the intestinal absorption of metformin, focusing on OCT3, PMAT, THTR2, SERT and OCTN2. We also assessed the impact of these transporters on the nonlinear absorption of metformin. Uptake studies with MDCKII cells expressing OCT3, PMAT, THTR2 or SERT confirmed that metformin is a substrate of these transporters. Decynium22 strongly inhibited metformin uptake mediated by all the transporters. 7-Cyclopentyl inhibited OCT3- and THTR2-mediated uptake of metformin. AG835, thiamine and paroxetine specifically inhibited PMAT-, THTR2- and SERT-mediated uptake of metformin, respectively. Using these inhibitors, the relative contributions of OCT3, PMAT, THTR2, SERT, OCTN2 and others to the intestinal permeation of metformin across Caco-2 cells were estimated to be 9.77%, 9.68%, 22.2%, 1.52%, 0% and 0.66%, respectively. Concentration-dependent analysis of metformin uptake by Caco-2 cells revealed nonlinear kinetics with the similar K m(app) value to the value for THTR2. Further in situ absorption study demonstrated that rat intestinal permeability of metformin was significantly decreased in the presence of decynium22, 7-cyclopentyl and thiamine. The present study indicated that THTR2 is the major determinant of the nonlinear absorption of metformin, although multiple transport mechanisms contribute to its intestinal absorption. [ABSTRACT FROM AUTHOR]

The Food and Drug Administration recommends rosuvastatin dosage reductions in Asian patients because pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects compared with Caucasian controls. Yet, no explanation for this ethnic difference has been confirmed. Here we show that rosuvastatin exposure in Asians and Whites does not differ significantly when all subjects are wild-type carriers for both solute carrier organic anion transporter 1B1 *1a and ATP-binding cassette subfamily G member 2 c.421 transporters in a 2-arm, randomized, cross-over rosuvastatin pharmacokinetics study in healthy white and Asian volunteers. For single rosuvastatin doses, AUC0-48 were 92.5 (±36.2) and 83.5 (±32.2) ng/mL × h and Cmax were 10.0 (±4.1) and 7.6 (±3.0) ng/mL for Asians and Whites, respectively. When transporters were inhibited by intravenous rifampin, rosuvastatin AUC0-48 and Cmax also showed no ethnic differences. Our study suggests that both SLCO1B1 and ABCG2 polymorphisms are better predictors of rosuvastatin exposure than ethnicity alone and could be considered in precision medicine dosing of rosuvastatin.

Although the functions of small intestine are largely regulated by enteric nervous system (ENS), an independent intrinsic innervation, as well as central nervous system (CNS), the neural regulation of drug absorption from the small intestine still remains to be clarified. To obtain some information on it, the effect of adrenergic agonists on P-glycoprotein (P-gp) function was investigated by utilizing a vascular-luminal perfused rat small intestine. Adrenaline significantly decreased the secretion of rhodamine-123 (R-123) into the intestinal lumen, but dibutyryl cAMP (DBcAMP) significantly enhanced R-123 secretion. The inhibition study with quinidine clearly indicated that the decrease in secretory clearance of R-123 by adrenaline or the increase by DBcAMP would be attributed to the decrease or increase in P-gp activity, respectively. Expression levels of P-gp in whole mucosal homogenates were not changed at all by any chemicals examined, but those on brush border membrane (BBM) of intestinal epithelial cells were significantly decreased or increased by adrenaline or DBcAMP, respectively. Furthermore, changes in P-gp activity caused by adrenergic agonists and DBcAMP were significantly correlated with changes in expression level of P-gp in BBM, suggesting that the trafficking of P-gp from cytosolic pool to BBM would be regulated by adrenergic agonists and DBcAMP. [ABSTRACT FROM AUTHOR]

To clarify the regulation of drug absorption by the enteric nervous system, we investigated how adrenergic agonists (adrenaline (ADR), clonidine (CLO), dobutamine (DOB)) and dibutyryl cAMP (DBcAMP) affected P-glycoprotein (P-gp) function by utilizing isolated rat jejunal sheets and Caco-2 cell monolayers. ADR and CLO significantly decreased the secretory transport (P app total ) of rhodamine-123 and tended to decrease the transport via P-gp (P app P-gp ) and passive transport (P app passive ). In contrast, DBcAMP significantly increased and DOB tended to increase P app total and both tended to increase P app P-gp and P app passive . Changes in P-gp expression on brush border membrane by adrenergic agonists and DBcAMP were significantly correlated with P app P-gp , while P-gp expression was not changed in whole cell homogenates, suggesting that the trafficking of P-gp would be responsible for its functional changes. P app passive was inversely correlated with transmucosal or transepithelial electrical resistance, indicating that adrenergic agonists affected the paracellular permeability. Adrenergic agonists also changed cAMP levels, which were significantly correlated with P app P-gp . Furthermore, protein kinase A (PKA) or PKC inhibitor significantly decreased P app P-gp in Caco-2 cell monolayers, suggesting that they would partly contribute to the changes in P-gp activity. In conclusion, adrenergic agonists regulated P-gp function and paracellular permeability, which would be caused via adrenoceptor stimulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.

The hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 min, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of coadministered drugs metabolized by these enzymes. Plasma protein-binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bidirectional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies.

This study aimed to prepare a nanoemulsion vehicle to improve the oral bioavailability of hesperetin. The pseudo-ternary phase diagrams and the RSM were used to optimize nanoemulsion parameters. Compared with hesperetin suspension, the AUC 0-t and C max of nanoemulsion were increased by 5.67-fold and 2.64-fold, respectively. The proportion of lymphatic transport reached 87.72%, the cumulative absorption amount of jejunum, ileum, and duodenum increased by 1.1-fold, 1.92-fold, and 1.5-fold, respectively. The results implied that hesperetin nanoemulsion could effectively improve the bioavailability of hesperetin by increasing lymphatic transport and enhancing intestinal permeability. Therefore, nanoemulsion is a potential method to improve the bioavailability of hesperetin, which has strong practicability. [ABSTRACT FROM AUTHOR]

Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro , were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C 10). Cyclic HAVN1 and ADTC5 peptides increased FD4 bioavailability by 7.2- and 4.4-fold compared to control, respectively (not statistically significant). In contrast, C 10 provided a statistically significant 10.7-fold relative bioavailability enhancement for FD4. Importantly, this study represents the first report of cyclic E-cadherin peptides as intestinal membrane permeation enhancers. The findings described herein demonstrate the potential of enzymatically stabilized cyclic E-cadherin peptides for increasing poorly permeable drug absorption via the oral route. [ABSTRACT FROM AUTHOR]

Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (f a) via the lymph in the fed state was 0.26, representing 62% of the increase in f a in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport. [ABSTRACT FROM AUTHOR]

To identify oral drugs that likely display nonlinear pharmacokinetics due to saturable metabolism by intestinal CYP3A, our previous report using CYP3A substrate drugs proposed an approach using thresholds for the linear index number (LIN3A = dose/K m ; K m , Michaelis-Menten constant for CYP3A) and the intestinal availability (F a F g). Here, we aimed to extend the validity of the previous approach using both CYP3A substrate and non-substrate drugs and to devise a decision tree suited for early drug candidates using in vitro metabolic intrinsic clearance (CL int, vitro) instead of F a F g. Out of 152 oral drugs (including 136 drugs approved in Japan, US or both), type I nonlinearity (in which systemic drug exposure increases in a more than dose-proportional manner) was noted with 82 drugs (54%), among which 58 drugs were identified as CYP3A substrates based on public information. Based on practical feasibility, 41 drugs were selected from CYP3A substrates and subjected to in-house metabolic assessment. The results were used to determine the thresholds for CL int, vitro (0.45 μL/min/pmol CYP3A4) and LIN3A (1.0 L). For four drugs incorrectly predicted, potential mechanisms were looked up. Overall, our proposed decision tree may aid in the identification of early drug candidates with intestinal CYP3A-derived type I nonlinearity. [ABSTRACT FROM AUTHOR]

This issue of the Journal of Pharmaceutical Sciences is dedicated to Professor Per Artursson and the groundbreaking contributions he has made and continues to make in the Pharmaceutical Sciences. Per is one of the most cited researchers in his field, with more than 30,000 citations and an h-index of 95 as of September 2020. Importantly, these citations are distributed over the numerous fields he has explored, clearly showing the high impact the research has had on the discipline. We provide a short portrait of Per, with emphasis on his personality, driving forces and the inspirational sources that shaped his career as a world-leading scientist in the field. He is a curious scientist who deftly moves between disciplines and has continued to innovate, expand boundaries, and profoundly impact the pharmaceutical sciences throughout his career. He has developed new tools and provided insights that have significantly contributed to today's molecular and mechanistic approaches to research in the fields of intestinal absorption, cellular disposition, and exposure-efficacy relationships of pharmaceutical drugs. We want to celebrate these important contributions in this special issue of the Journal of Pharmaceutical Sciences in Per's honor. [ABSTRACT FROM AUTHOR]

The development of multiple drug modalities over the past 20 years has dramatically expanded the therapeutic space for intervention in disease processes. Rather than being alternative therapeutic approaches, these modalities tend to be complimentary both in the scope of target space and the biological mechanisms harnessed for disease control. Realization of these therapeutic opportunities requires an understanding of the physiological, biochemical and biological barriers that control exposure to the drug target and resulting biological response. Consequently, successful application of ADME and PK/PD to characterization of novel therapeutics needs to consider the unique attributes conferred by the therapeutic modality and the desired and potential off-target biological responses. The discussion that follows provides examples of how barriers to exposure, and translation of exposure to efficacy can change across different modalities. Additionally, recommendations are made for ADME analysis in which biological barriers and mechanistic properties unique to specific modalities are used to focus ADME PK optimization and characterization. Preface: It is an honor to contribute to this issue of Journal of Pharmaceutical Science recognizing Per Artursson and his many accomplishments as a scientist and an educator. Meeting Per at a conference in 1989, I was impressed by his scientific agility, enthusiasm and breadth of knowledge. He showed a passion for science and courage to jump into unfamiliar scientific waters with research extending from microsphere formulations, the biology of drug absorption, cell biology of junctional complexes, delivery tools for gene therapy, and physicochemical analysis of structure transport relationships guiding intestinal absorption. Per has approached all these efforts with infectious enthusiasm, depth of knowledge, and a big smile. He shares his insights with students and colleagues leaving a path of wisdom to be followed. In recognition of Per's adaptability and enthusiasm toward incorporating diverse strategies to address key challenges in the discovery and characterization of therapeutic molecules, I am happy to contribute this commentary on adapting ADME/PK characterization to address the novel challenges of emerging modalities. [ABSTRACT FROM AUTHOR]

Mixed lipid aggregates, comprising of bile salts and phospholipids, present in the small intestine assist in drug solubilization and subsequent drug dissolution and absorption through the intestinal epithelium. The increased variability in their levels, observed physiologically, may create challenges not only for in vivo bioavailability and bioequivalence studies, but also for in vitro bio-predictive studies as correlations between in vitro and in vivo data are not always successful. The current study investigated the impact of biorelevant dissolution media, with physiologically relevant sodium taurocholate and lecithin levels, on the apparent solubility and affinity of lipophilic compounds with a wide range of physicochemical properties (drug ionization, drug lipophilicity, molecular weight) to mixed lipid aggregates. Apparent solubility data in biorelevant dissolution media for the studied neutral drugs, weak bases and weak acids were compared against a phosphate buffer pH 6.5 in the absence of these lipidic components. Presence of mixed lipid aggregates enhanced the apparent solubility of the majority of compounds and the use of multivariate data analysis identified the significant parameters affecting drug affinity to mixed lipid aggregates based on the chemical class of the drug. For neutral drugs, increasing bile salt concentrations and/or drug lipophilicity resulted in greater enhancement in apparent solubility at 24-hr. For weak bases and weak acids, the effect of increasing bile salt levels on apparent solubility depended mostly on an interplay between drug lipophilicity and drug ionization. [ABSTRACT FROM AUTHOR]

NSAIDs such as celecoxib and sulindac play a critical role in the treatment of colorectal cancer, yet it is not understood how sufficiently high concentrations are reached in colonic tissue. We previously demonstrated that an incomplete small intestinal absorption of celecoxib enables gut driven drug accumulation in caecal tissue, which is most likely needed for inducing remission. However, a multistage dissolution experiment suggested a more extensive absorption of sulindac relative to celecoxib, though still incomplete. To study whether caecal accumulation of sulindac is solely plasma driven or also gut driven, we performed an exploratory clinical study in healthy volunteers. After intake of a tablet of sulindac (200 mg; Arthrocine), two colonoscopies (1.0–2.5 h, and 6.0–7.5 h after drug intake) were performed to assess concentrations of sulindac and metabolites in plasma, caecal tissue and caecal contents. We observed that sulindac, even without the use of a colon-targeted delivery strategy, can arrive at the colonic lumen due to incomplete absorption and biliary excretion, and that the microbiota can catalyse the production of sulindac sulfide, which then accumulates in a high and local manner in the colonic tissue. These data can be relevant for drug development in the treatment of colorectal adenomas and cancer. [ABSTRACT FROM AUTHOR]

Phospholipids are amphiphilic lipids with versatile properties making them promising excipients for enabling formulations for oral drug delivery. Unfortunately, systematic studies on how phospholipid type and content affect oral absorption are rare. Often, only one phospholipid type is used for the formulation development and only one formulation, optimized according to in vitro parameters, is included in oral bioavailability studies. Using this approach, it is unclear if a certain in vitro parameter is predictive for the in vivo performance. In this study, a labor-saving in vitro permeation screening method was combined with a pharmacokinetic study in rats to for the first time systematically compare two types of phospholipid-based solid dispersions. The dispersions contained the drug celecoxib and monoacyl or diacyl phosphatidylcholine at different drug-to-phospholipid ratios. The in vitro screening revealed: 1) none of the formulations with high phospholipid content increased permeation, 2) phospholipid content was negatively correlated with permeation, and 3) mono and diacyl-phosphatidylcholine formulations performed equally. The pharmacokinetic study revealed: 1) At low phospholipid content absorption was enhanced, 2) phospholipid content was negatively correlated with absorption, and 3) monoacyl and diacyl phosphatidylcholine formulations performed equally. Apart from the reference (suspension), the in vitro permeation screening thus predicted the formulations in vivo performance. [ABSTRACT FROM AUTHOR]

The proton-coupled amino acid transporter, PAT1, is known to be responsible for intestinal absorption drug substances such as gaboxadol and vigabatrin. The aim of the present study was to investigate, if 17-α-ethinyl-estradiol (E-E2) and 17-β-estradiol (E) inhibit PAT1-mediated intestinal absorption of proline and taurine in vitro in Caco-2 cells and in vivo using Sprague-Dawley rats to assess the potential for taurine-drug interactions. E and E-E2 inhibited the PAT1-mediated uptake of proline and taurine in Caco-2 cells with IC 50 values of 10.0–50.0 μM without major effect on other solute carriers such as the taurine transporter (TauT), di/tri-peptide transporter (PEPT1), and serotonin transporter (SERT1). In PAT1-expressing oocytes E and E-E2 were non-translocated inhibitors. In Caco-2 cells, E and E-E2 lowered the maximal uptake capacity of PAT1 in a non-competitive manner. Likewise, the transepithelial permeability of proline and taurine was reduced in presence of E and E-E2. In male Sprague Dawley rats pre-dosed with E-E2 a decreased maximal plasma concentration (C max) of taurine and increased the time (t max) to reach this was indicated, suggesting the possibility for an in vivo effect on the absorption of PAT1 substrates. In conclusion, 17-α-ethinyl-estradiol and 17-β-estradiol were identified as non-translocated and non-competitive inhibitors of PAT1. [ABSTRACT FROM AUTHOR]

Intestinal absorption of orally administered peptides is often negligible because one or more key requirements for successful absorption (water solubility, peptic resistance, mucosal permeation) are not met. Due to its high water solubility and stability in the gastro-intestinal tract, vancomycin is an ideal model peptide for evaluating the factors influencing the critical step of mucosal permeation. Therefore, to support formulation development for the systemic oral delivery of peptide therapeutics, we investigated the pharmacokinetics of vancomycin in beagle dogs after intravenous and oral administration comparing enteric encapsulated drug to the drug in solution, which revealed mean absolute bioavailabilities of 0.27% and 1.66%, respectively. Additionally, in depth pharmacokinetic analyses of intravenously administered vancomycin revealed a deep compartment slowly releasing the compound over many hours into the blood. [ABSTRACT FROM AUTHOR]

Excipients used in drug formulations at clinically safe levels have been considered to be pharmacologically inert; however, numerous studies have suggested that many solubilizing agents may modulate drug transporter activities and intestinal absorption. Here, the reported interactions between various solubilizing excipients and drug transporters are evaluated to consider various potential underlying mechanisms. This forms the basis for debate in the field in regard to whether or not the effects are based on "direct" interactions or "indirect" consequences arising from the role of the excipients. For example, an increase in apparent drug solubility can give rise to saturation of transporters according to Michaelis-Menten kinetics. This is also drawing the attention of regulatory agencies as they seek to understand the role of formulation additives. The continued application of excipients as a tool in solubility enhancement is crucial in the drug development process, creating a need for additional data to verify the proposed mechanism behind these changes. A literature review is provided here with some guidance on other factors that should be considered to delineate the effects that arise from direct physiological interactions or indirect effects. The results of such studies may aid the rational design of bioavailability-enhancing formulations. [ABSTRACT FROM AUTHOR]

None of the physiologically based pharmacokinetic (PBPK) approaches using preclinical data show high predictability of human pharmacokinetic (PK) profiles for drugs affected by the intestinal first-pass effect. Here we report a novel PBPK approach that incorporated the findings of a permeation study using human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs) to predict human PK profiles after oral administration of drugs. In hiPSC-IECs, gene expression levels of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are enhanced by rifampicin and 1,25-dihydroxyvitamin D 3. The permeability of 24 drugs (10 test drugs and 14 reference drugs), including CYP3A4 and P-gp substrates, correlated highly with gastrointestinal availability (F a × F g), and could be converted to the apparent absorption rate constant (k a, app) based on the correlation between F a × F g and in vivo k a of 27 drugs. The k a, app was input into the PBPK model which contained the optimized calculation processes of metabolism and tissue distribution. The absolute average fold error of PK parameters such as maximum plasma concentration and bioavailability for test drugs was less than 2, suggesting that human PK profiles could be predicted with high accuracy. Our robust PBPK approach enables quick decision-making in drug discovery based on human PK profiles. [ABSTRACT FROM AUTHOR]

Sodium caprate (C10) acts as an absorption enhancer. However, the absorption-enhancing effects of compounds with structures similar to C10 have not been characterized. In the present study, insulin was used as a model drug. We examined the effects of C10 and its related compounds on intestinal absorption of insulin using an in situ closed loop in rats. Insulin absorption was significantly enhanced by propylene glycol caprylate (Sefsol-218), a C10-related compound, after large intestinal administration. In addition, activity of lactate dehydrogenase did not increase in the intestinal epithelium in the presence of Sefsol-218 at concentrations equivalent to or lower than 1% (v/v). However, a significant increase in lactate dehydrogenase activity was observed in response to C10. These findings suggested that Sefsol-218 was safer than C10. Furthermore, mechanistic studies showed that increased membrane fluidity and loosening of tight junctions (TJs) might be underlying mechanisms by which this compound improved intestinal absorption of insulin. Furthermore, Sefsol-218 opened TJs by reducing the expression of claudin-4, which is a major TJ protein. These findings suggested that Sefsol-218 effectively enhanced intestinal insulin absorption without causing serious damage to the intestinal epithelium. [ABSTRACT FROM AUTHOR]

Eflornithine has been used to treat second-stage human African trypanosomiasis. However, it has inadequate oral bioavailability and low blood-brain barrier permeation, thus requiring a lengthy and complicated intravenous infusion schedule. Here, we investigated the feasibility of using an intercellular junction-modulating E-cadherin peptide HAV6 to enhance the oral bioavailability and blood-brain barrier permeation of eflornithine. Eflornithine was not metabolized in liver microsomes, nor was it a substrate for the human efflux transporter P-glycoprotein. Furthermore, HAV6 and HAV6scr (sequence scrambled HAV6) were stable in simulated gastric fluid with pepsin and rat intestinal mucosal scrapings. Both peptides were stable in human plasma, albeit less stable in rat and mouse plasma. HAV6 increased eflornithine permeability across Madin-Darby canine kidney and Caco-2 cell monolayers (5- and up to 8.5-fold), whereas HAV6scr had little effect. Using an in situ rat brain perfusion model, HAV6, but not HAV6scr, significantly increased eflornithine concentrations in different brain regions up to 4.9-fold. In rats, coadministration of HAV6 increased eflornithine oral bioavailability from 38% to 54%, brain concentrations by up to 83%, and cerebrospinal fluid concentrations by 40%. In conclusion, coadministration of HAV6, either during intravenous infusion or as an oral formulation, has the potential to improve eflornithine-based treatment for second-stage human African trypanosomiasis. [ABSTRACT FROM AUTHOR]

Absorption of drugs is the first step after dosing, and it largely affects drug bioavailability. Hence, estimating the fraction of absorption (Fa) in humans is important in the early stages of drug discovery. To achieve correct exclusion of low Fa compounds and retention of potential compounds, we developed a freely available model to classify compounds into 3 levels of Fa capacity using only the chemical structure. To improve Fa prediction, we added predicted binary classification results of membrane permeability measured using Caco-2 cell line (Papp) and dried–dimethyl sulfoxide solubility (accuracy, 0.836; kappa, 0.560). The constructed models can be accessed via a web application. [ABSTRACT FROM AUTHOR]

The viscous and elastic mucus layer is still an undesirable barrier for oral insulin delivery. To solve the problem, virus-mimicking nanosized polyelectrolyte complex (PEC) was designed and their capacity in enhancing peroral insulin absorption in combination with bifunctional material sodium dodecyl sulfate (SDS) coating was investigated. Inspired by nature, virus-mimicking chitosan (CS)-modified L-Phe derivatives were synthesized to simulate the components of viral envelopes and then PECs between CS-g-N-Phe copolymers and insulin were prepared to achieve both structure and composition simulation of virus envelope. Based on the results from both in vitro and in vivo studies, it was concluded that in vitro mucodiffusion and in vivo hypoglycemic effect were dependent on L-Phe graft ratio, with CS-g-N-Phe 20.2% /insulin PECs presenting 2.0- to 2.2-fold higher relative pharmacological bioavailability than nonmodified CS/insulin PECs. Thereafter, SDS solution was applied as outer layer coating on the surface of virus-mimicking PECs. The coated PECs showed improved enzymatic stability, enhanced transport across mucus layer as well as intestinal epithelium in an SDS concentration–dependent manner, with 0.6% SDS coating presenting the best effect, with further enhanced relative pharmacological bioavailability in healthy rats and prolonged therapeutic effect up to 9 h. [ABSTRACT FROM AUTHOR]

Liver dysfunction reduces systemic clearance of drugs that are primarily eliminated by the liver. However, liver dysfunction can cause a reduction in the plasma concentration profiles of certain drugs, including several tyrosine kinase inhibitors, after oral administration. The aim of the present study was to clarify the reduction in oral absorption of a tyrosine kinase inhibitor, imatinib, and the mechanisms of action involved under conditions of hepatic dysfunction, focusing on intestinal transporters. The maximum plasma concentration of imatinib after oral administration in mice subjected to bile duct ligation (BDL) was lower than that in sham-operated mice, whereas the plasma concentration profile after intravenous administration was essentially unaffected by BDL. The change in maximum plasma concentration was compatible with a reduction in small intestinal permeability of imatinib observed in the in situ closed loop. Gene expression of abcg2 was increased in BDL mice compared with that in sham-operated mice. Expression of breast cancer resistance protein and P-glycoprotein in the small intestinal brush border membrane fraction from BDL mice was also increased compared with that in sham-operated mice. In summary, the intestinal absorption and permeability of imatinib was decreased in BDL mice, and this may be attributed to the up-regulation of the efflux transporter(s). [ABSTRACT FROM AUTHOR]

The purpose of the present study was to evaluate the prediction accuracy of a mechanism-based oral absorption model for the fraction of a dose absorbed (Fa) in dogs, focusing on poorly soluble drugs. As an open mechanism-based model, the gastrointestinal unified theoretical framework was used in this study. The prediction accuracy of the gastrointestinal unified theoretical framework was evaluated using Fa data in dogs (63 data sets for marketed drugs and proprietary compounds). For neutral compounds, Fa was accurately predicted, suggesting that the physiological parameters of dogs were appropriate except for gastrointestinal pH. An extensive literature survey on the small intestinal pH of dogs was then conducted. The result suggested that the pH value ranged between 6.5 and 7.5, with the midst value of 7.0, but there was a great variation among the literature. To confirm the appropriateness of this pH value, the Fa of free acid compounds was predicted by setting the small intestinal pH to 6.5, 7.0, and 7.5. The proportions of compounds with <2-fold error were 57%, 90%, and 76%, respectively. The results of the present study would enable an appropriate use of a mechanism-based model for drug discovery and development. [ABSTRACT FROM AUTHOR]

Proteins and peptides are poorly absorbed via oral administration because of the gastrointestinal tract environment and lysosomal digestion after apical endocytosis. A delivery system, consisting of a deoxycholic acid–conjugated nanometer-sized carrier, may enhance the absorption of proteins in the intestine via the bile acid pathway. Deoxycholic acid is first conjugated to chitosan. Liposomes are then prepared and loaded with the model drug insulin. Finally, the conjugates are bound to the liposome surface to form deoxycholic acid and chitosan conjugate–modified liposomes (DC-LIPs). This study demonstrates that DC-LIPs can promote the intestinal absorption of insulin via the apical sodium-dependent bile acid transporter, based on observing fluorescently stained tissue slices of the rat small intestine and a Caco-2 cell uptake experiment. Images of intestinal slices revealed that excellent absorption of DC-LIPs is achieved via apical sodium-dependent bile acid transporter, and a flow cytometry experiment proved that DC-LIPs are a highly efficient delivery carrier. Caco-2 cells were also used to study the lysosome escape ability of DC-LIPs. We learned from confocal microscopy photographs that DC-LIPs can protect their contents from being destroyed by the lysosome. Finally, according to pharmacokinetic analyses, insulin-loaded DC-LIPs show a significant hypoglycemic effect with an oral bioavailability of 16.1% in rats with type I diabetes. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer resistance protein transporter (ABCG2/BCRP) is highly expressed on the intestinal epithelial membrane and has a significant impact on the oral absorption of topotecan. In this study, we examined 6 pharmaceutical excipients including BL-9EX, Brij97, Cremophor EL, Labrasol, Pluronic F68, and Tween 20 for their BCRP inhibitory effects. A bidirectional transport study using Caco-2 cells demonstrated that Tween 20 and Cremophor EL significantly increased the absorptive transport of topotecan, while simultaneously decreasing secretory transport. Interestingly, Labrasol selectively increased absorptive transport, whereas Pluronic F68 selectively decreased the secretory transport, of topotecan. Further investigation using an in situ closed loop experiment showed that 0.05% (w/v) Tween 20 and Cremophor EL significantly increased the intestinal absorption of topotecan in rats. An LDH assay demonstrated that 0.05% (w/v) Tween 20 and Cremophor EL did not cause significant damage to intestinal epithelial membranes. Furthermore, we examined the absorption-enhancing mechanisms of these excipients and found that Cremophor EL, Tween 20, and Labrasol increased the membrane fluidity of the inner lipid bilayers of the intestine. Therefore, this might be one of the most important mechanisms for inhibition of BCRP function by these excipients in the intestine. [ABSTRACT FROM AUTHOR]

Abstract Intestinal transporters and metabolizing enzymes are the important factors of the intestinal absorption barrier. Because there is evidence that their expression and function may be affected during inflammatory conditions, we investigated gene expression, protein abundance, and regulation of relevant intestinal transporters and metabolizing enzymes in the intestinal mucosa of patients with ulcerative colitis (UC). Specimens from inflamed and noninflamed tissues of 10 patients with UC as well as colonic control tissues of 10 patients without inflammation were subjected to gene (9 enzymes, 15 transporters, 9 cytokines) and microRNA (N = 54) expression analysis. Protein abundance was quantified by liquid chromatography-tandem mass spectrometry–based targeted proteomics. Gene expression of several metabolizing enzymes (e.g., CYP2C9, UGT1A1) and transporters such as ABCB1 (ABCB1), ABCG2 (ABCG2), and monocarboxylate transporter 1 (MCT1, SLC16A1) were significantly decreased during inflammation and negatively correlated to microRNAs. On contrary, multidrug resistance-protein 4 (MRP4, ABCC4), organic anion–transporting polypeptide 2B1 (OATP2B1, SLCO2B1), and organic cation transporter-like 2 (ORCTL2, SLC22A18) were significantly elevated in inflamed tissue. However, at protein level, these findings could only be confirmed for MCT1. UC is associated with complex changes in the intestinal expression of enzymes, transporters, cytokines, and microRNAs, which may affect efficacy of anti-inflammatory drug therapy or the disease state itself. [ABSTRACT FROM AUTHOR]

Abstract SPRYCEL® (Dasatinib) is a Biopharmaceutical Classification System II weakly basic drug that exhibits strong pH-dependent solubility. Dasatinib is currently presented in 2 drug product formulations as an adult immediate release tablet and a pediatric powder for oral suspension. A bioequivalence study comparing the formulations in adult healthy subjects found that overall exposure (AUC 0-24) from suspension treatments was ∼9% to 13% lower, Cmax was similar, and median Tmax from powder for oral suspension was ∼30 min earlier. To understand the mechanism contributing to this behavior, a combination of biorelevant dissolution studies and physiologically based pharmacokinetic modeling was used to simulate in vivo performance. In vitro biorelevant dissolution confirmed that the rate and extent of release was similar between tablet and suspension formulations (>90% release within first 15 min). Physiologically based pharmacokinetic parameter sensitivity analysis demonstrated particular sensitivity to dosage form gastric residence time. A 12% higher AUC 0-24 was simulated for tablet dosage forms with 10 to 15 min longer gastric transit relative to solutions or suspensions of small particulates (rapid gastric emptying). The corresponding narrow simulated Cmax range also agreed with observed tablet and suspension bioequivalence data. The unique physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior are attributed to influence the dasatinib bioequivalence. [ABSTRACT FROM AUTHOR]

Abstract The purpose of this study was to investigate the possibility of simultaneous prediction of the intestinal absorption and metabolism in a mini-Ussing chamber equipped with rat intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts, by mass balance method, transported to the basal-side component and drug amounts accumulated in the tissue, which are normalized by area under the curve of the drug in the apical compartment. Midazolam and nifedipine with high permeability were used as typical P450 substrates to examine the possibility of simultaneous prediction of intestinal absorption and metabolism. The metabolite formation of both compounds was observed and ketoconazole strongly inhibited the metabolite formation of both compounds in rat intestinal tissues, leading to the improvement of the TI value to a statistically significant extent for both compounds. TI ratio of nifedipine between in the presence and absence of ketoconazole was larger than that of midazolam, which was consistent with the reported lower value of fraction absorbed multiplied by intestinal availability of nifedipine. Therefore, the mini-Ussing chamber, equipped with animal intestinal tissues, showed potential to predict the intestinal absorption and metabolism simultaneously. [ABSTRACT FROM AUTHOR]

Abstract The unique character of bile salts to self-assemble into hydrogels in the presence of halide salts was exploited in this work to facilitate the prediction of human intestinal absorption (%HIA) for a set of 25 compounds. This was achieved by firstly incorporating each compound separately within the process of gel formation to create a series of gel-drug membranes. Scanning electron microscopy analysis of the freeze-dried samples of the blank bile salt hydrogels and drug-loaded bile salt hydrogels indicated a unique microstructure made of a network of intertwined fibrils. Drug-loaded sodium deoxycholate hydrogels were then utilized as the donor phase to study permeability using flow-through and static diffusion cells. The resulting values of the release-permeability coefficient (K p) were then analyzed, along with other molecular descriptors, for the %HIA using multiple linear regression. Overall, when comparing predicted values (using the systems presented in this study) with known literature values, it can be seen that both methods (i.e., using static and flow-through cells) had good predictability with R2 PRED values of 79.8% and 79.7%, respectively. This study therefore proposes a novel, accurate, and precise way to predict HIA for compounds of pharmaceutical interest using a simple in vitro permeation system. It is important to develop alternatives to the current methods used in prediction of HIA, which are expensive and time-consuming or include the use of animals. Therefore, the proposed method in this study being economic and time-saving provides superiority over these current methods and suggests the possibility of its use as an alternate to such methods for prediction of HIA. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer resistance protein (BCRP) transporter is an efflux transporter that utilizes energy from adenosine triphosphate hydrolysis to push its substrates, regardless of the concentration gradient. Its presence on the apical membrane of the intestinal mucosa is a major obstacle for the intestinal absorption of its substrates. In this study, we examined the effects of various pharmaceutical excipients on the intestinal transport and absorption of sulfasalazine, a BCRP substrate. Four excipients, including 0.05% and 0.075% BL-9EX, 0.01% and 0.05% Brij 97, 0.075% Labrasol, and 0.05% and 0.1% Tween 20 decreased the secretory transport of sulfasalazine in an in vitro diffusion chamber. Further investigation in an in situ closed loop experiment in rats showed that 0.05% and 0.1% BL-9EX and 0.1% Brij 97 effectively enhanced the intestinal absorption of sulfasalazine while maintaining minimal toxicity to the intestinal mucosa. However, 0.1% Brij 97 also increased the intestinal absorption of 5(6)-carboxyfluorescein, a paracellular marker compound. These findings suggest that BL-9EX might effectively inhibit the BCRP-mediated efflux of sulfasalazine in vivo , indicating that BL-9EX could improve the intestinal absorption of sulfasalazine and other BCRP substrates. [ABSTRACT FROM AUTHOR]

Advanced compartmental absorption and transit (ACAT) based computational models have become increasingly popular in the industry for predicting oral drug product performance. However, due to its complexity, some compromises have been made in practice, and the stomach is often assigned as a single compartment. Although this assignment worked generally, it may not be sufficient to reflect the complexity of the gastric environment under certain conditions. For example, this setting was found to be less accurate in estimating stomach pH and solubilization of certain drugs under food intake, which leads to a misprediction of the food effect. To overcome the above, we explored the use of a kinetic pH calculation (KpH) for the single-compartment stomach setting. Several drugs have been tested with the KpH approach and compared with the default setting of Gastroplus. In general, the Gastroplus prediction of food effect is greatly improved, suggesting this approach is effective in improving the estimation of physicochemical properties related to food effect for several basic drugs by Gastroplus., Competing Interests: Conflict of Interest The authors declare no conflict of interest in this work, (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Fluoropyrimidines, including 5-fluororacil (5-FU), cause gastrointestinal damage in the clinical setting and might affect the gastrointestinal absorption of concomitantly administered drugs. We aimed to evaluate the effects of fluoropyrimidine-induced gastrointestinal damage on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DABE), an anticoagulant, in rats with gastrointestinal damage induced by the repeated oral administration of 5-FU. Rats were administered DABE orally or dabigatran (DAB), an active moiety of DABE, intravenously. The plasma DAB concentration was determined using liquid chromatography-tandem mass spectrometry. The activated partial thromboplastin time (APTT) was measured before and 30 min after the administration of each drug, and the APTT ratio was calculated. In 5-FU-treated rats, the maximum plasma concentration, the area under the concentration-time curve of DAB after the oral administration of DABE, and the oral bioavailability of DABE were significantly decreased to 18.3%, 22.9%, and 16.3% of the respective control values. The 5-FU-treated rats' APTT ratio was also significantly lower than the control value. Fluoropyrimidine-induced gastrointestinal damage might reduce the plasma concentration of DAB by impairing DABE absorption and might attenuate the anticoagulant effects of DABE in the clinical setting. [ABSTRACT FROM AUTHOR]

The aim of this study was to improve the oral absorption of epidermal growth factor receptor–targeted hybrid peptide using bile acid as an absorption enhancer. The oral formulation of this peptide was formed through electrostatic interactions between the cationic peptide and anionic bile acid. Comparative studies of in vitro cell permeability and in vivo antitumor effects of peptide and peptide/bile acid complex were performed in Caco-2 cells and in a xenograft mouse model of human gastric cancer. The in vitro permeability of peptide/bile acid complex across Caco-2 cell monolayers was significantly enhanced to about 5.0-fold over those of peptide alone. Furthermore, in vivo mouse xenograft model treated with peptide/bile acid complex showed a 1.6-fold reduction in the mean tumor volume as compared with the peptide alone. A preliminary safety evaluation of blood cells counts, liver enzyme levels, and histopathology of gastrointestinal tissues and main organs showed that the peptide/bile acid complex did not induce any acute toxicity. These results suggest that bile acid is an effective absorption enhancer for improving the oral bioavailability and bioactivity of epidermal growth factor receptor–targeted hybrid peptide. [ABSTRACT FROM AUTHOR]