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Although arthralgia is a known adverse effect of aromatase inhibitor (AI) treatment in postmenopausal breast cancer patients, few studies have carried out a comprehensive evaluation of the nature, onset, and incidence of musculoskeletal (MSK) pain in these patients. We therefore used a pilot study to identify conditions or markers predictive of pain. Methods For 24 weeks, we monitored 30 eligible postmenopausal women starting AI therapy. Pre-existing and incident MSK conditions and pain were assessed clinically and with ultrasonography of the hands and wrists. In addition, patient questionnaires were used to assess pain before and during ai therapy. Biochemical markers were measured at baseline and at regular intervals after anastrozole therapy began. Gene profiling studies were carried out before and 48 hours after the initial AI administration. Results Over the 24-week study period, 20 participants (67%) showed no pain symptoms; 5 (17%) experienced low or moderate pain at baseline, which did not increase with ai treatment; and during therapy, 5 (17%) showed exacerbation of pain attributable to osteoarthritis of the hand and to finger flexor tenosynovitis. Although all 30 participants had some degree of MSK conditions before anastrozole therapy started, the pre-existing conditions did not necessarily predispose the women to increased pain during anastrozole treatment. Higher levels of urinary N-telopeptides of type I collagen were associated with the groups presenting pain, suggesting a higher extent of pre-existing bone resorption, without significant evolution over the 24-week treatment period. Slightly higher levels of 1,25(OH)2 vitamin D3 were observed at baseline in patients with pain increase, but did not significantly change during treatment; however, average levels of 25(OH) vitamin D3 increased, likely because of supplementation. Although biochemical markers did not discriminate efficiently between pain groups, a signature of 166 genes in peripheral blood mononuclear cells was identified that could stratify patients into the various groups observed in this pilot study. The gene signature was enriched in components of inflammatory signalling and chemokine expression, of antitumoural immunity pathways, and of metabolic response to hormones and xenobiotics, although no clinically significant association could be made in the present study, considering the small number of patients. Nevertheless, the observed trend suggests the feasibility of developing surrogate predictive markers of MSK pain. Patient compliance was high in this study and was not affected by pain exacerbation. Conclusions Baseline MSK assessment showed pre-existing causes for pain in most of the study patients before initiation of the ai. Exacerbation of existing osteoarthritis pain and tenosynovial symptoms was the primary cause of pain increase. Musculoskeletal pain assessment at baseline and prompt treatment of pain symptoms may help to optimize adherence to AI therapy. The value of routinely assessing inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate was not supported by our pilot study. Gene expression profiles in peripheral blood mononuclear cells may be further explored in larger-scale studies as stratification markers to identify patients at risk of developing arthralgia. [ABSTRACT FROM AUTHOR]

The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 ( p = 0.004) and CYP2C19 ( p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 ( p = 0.001) increased, and a trend was observed for CYP3A5 ( p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum ( p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum ( p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.

Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor ( OPRM1 ). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The CYP2D6 gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to OPRM1 variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for CYP2D6 with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy.

(1) Background: Regular contact with a medication therapy management (MTM) pharmacist is shown to improve patients' understanding of their condition; however, continued demonstration of the value of a pharmacist delivered comprehensive medication review (CMR) using enhanced MTM services via telehealth is needed. The study aimed to describe a pilot program designed to improve type 2 diabetes mellitus (T2DM) management through enhanced condition specific MTM services. (2) Methods: This retrospective study included patients with T2DM aged 40-75 years who received a pharmacist-delivered CMR between January and December 2018. An evaluation of glycosylated hemoglobin (HbA1c) values 3 months pre- and post-CMR was performed. Wilcoxon signed-rank and chi-square tests were used. (3) Results: Of 444 eligible patients, a majority were female (58%) with a median age of 70 years. Median HbA1c values post-CMR were lower than pre-CMR (median 7.1% range 4.5-13.6; median 7.4% range 4.5-13.9, respectively; p = 0.009). There were fewer participants with HbA1c >9% post-CMR ( n = 66) than pre-CMR ( n = 80; p < 0.001) and more with HbA1C <6.5% post-CMR ( n = 151) than pre-CMR ( n = 130; p < 0.001). (4) Conclusion: This program evaluation highlighted the value of an enhanced condition specific MTM service via telehealth. Patients had improved HbA1c values three months after receiving a single pharmacist delivered CMR.

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.

The blood-brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, age, and age-associated disorders may alter the expression level and functionality of transporter protein elements that modulate drug distribution and accumulation into the brain, namely, drug efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions and diseases such as Alzheimer's disease, epilepsy, and stroke on the expression and functionality of the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their impact on drug efficacy and toxicity.

Fluoxetine is still one of the most widely used antidepressants in the world. The drug is extensively metabolized by several cytochrome P450 (CYP450) enzymes and subjected to a myriad of CYP450-mediated drug interactions. In a multidrug regimen, preemptive mitigation of drug-drug interactions requires knowledge of fluoxetine actions on these CYP450 enzymes. The major metabolic pathway of fluoxetine leading to the formation of its active metabolite, norfluoxetine, is mediated by CYP2D6. Fluoxetine and norfluoxetine are strong affinity substrates of CYP2D6 and can inhibit, potentially through various mechanisms, the metabolism of other sensitive CYP2D6 substrates. Remarkably, fluoxetine-mediated CYP2D6 inhibition subsides long after fluoxetine first passes through the liver and even remains long after the discontinuation of the drug. Herein, we review pharmacokinetic and pharmacogenetic information to help us understand the mechanisms underlying the prolonged inhibition of CYP2D6 following fluoxetine administration. We propose that long-term inhibition of CYP2D6 is likely a result of competitive inhibition. This is due to strong affinity binding of fluoxetine and norfluoxetine to the enzyme and unbound fluoxetine and norfluoxetine levels circulating in the blood for a long period of time because of their long elimination half-life. Additionally, we describe that fluoxetine is a CYP2C9 substrate and a mechanism-based inhibitor of CYP2C19.

In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug-drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme-intermediate complex that irreversibly reduces enzyme activity. This type of inhibition can cause interactions with drugs such as omeprazole, paroxetine, macrolide antibiotics, or mirabegron. A good understanding of mechanism-based inhibition and proper clinical management is needed by clinicians when such drugs are prescribed. It is important to recognize mechanism-based inhibition since it cannot be prevented by separating the time of administration of the interacting drugs. Here, we provide a comprehensive overview of the different types of mechanism-based inhibition, along with illustrative examples of how mechanism-based inhibition might affect prescribing and clinical behaviors.

Background: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 ( GSTA1 ) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation., Methods: This is a quasi-experimental retrospective study in adult patients ( n = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients' files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared., Results: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype ( p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A , 50% for *A/*B, and 65% for *B/*B . The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs., Conclusion: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies.

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with ( n = 20) or without ( n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein -1 min -1 ) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D ( p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

To limit effluent impacts on eutrophication in receiving waterbodies, a small community water resource recovery facility (WRRF) upgraded their conventional activated sludge treatment process for biological nutrient removal, and considered enhanced primary settling and anaerobic digestion (AD) with co-digestion of high strength organic waste (HSOW). The community initiated the resource recovery hub concept with the intention of converting an energy-consuming wastewater treatment plant into a facility that generates energy and nutrients and reuses water. We applied life cycle assessment and life cycle cost assessment to evaluate the net impact of the potential conversion. The upgraded WRRF reduced eutrophication impacts by 40 percent compared to the legacy system. Other environmental impacts such as global climate change potential (GCCP) and cumulative energy demand (CED) were strongly affected by AD and composting assumptions. The scenario analysis showed that HSOW co-digestion with energy recovery can lead to reductions in GCCP and CED of 7 and 108 percent, respectively, for the upgraded WRRF (high feedstock-base AD performance scenarios) relative to the legacy system. The cost analysis showed that using the full digester capacity and achieving high digester performance can reduce the life cycle cost of WRRF upgrades by 15 percent over a 30-year period., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Many drugs can cause unexpected muscle disorders, often necessitating the cessation of an effective medication. Inhibition of monocarboxylate transporters (MCTs) may potentially lead to perturbation of l-lactic acid homeostasis and muscular toxicity. Previous studies have shown that statins and loratadine have the potential to inhibit l-lactic acid efflux by MCTs (MCT1 and 4). The main objective of this study was to confirm the inhibitory potentials of atorvastatin, simvastatin (acid and lactone forms), rosuvastatin, and loratadine on l-lactic acid transport using primary human skeletal muscle cells (SkMC). Loratadine (IC 50 31 and 15 µM) and atorvastatin (IC 50 ~130 and 210 µM) demonstrated the greatest potency for inhibition of l-lactic acid efflux at pH 7.0 and 7.4, respectively (~2.5-fold l-lactic acid intracellular accumulation). Simvastatin acid exhibited weak inhibitory potency on l-lactic acid efflux with an intracellular lactic acid increase of 25-35%. No l-lactic acid efflux inhibition was observed for simvastatin lactone or rosuvastatin. Pretreatment studies showed no change in inhibitory potential and did not affect lactic acid transport for all tested drugs. In conclusion, we have demonstrated that loratadine and atorvastatin can inhibit the efflux transport of l-lactic acid in SkMC. Inhibition of l-lactic acid efflux may cause an accumulation of intracellular l-lactic acid leading to the reported drug-induced myotoxicity., Competing Interests: The authors declare no conflict of interest.

Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals ( n = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes. Expression levels of cyp3a11 and cyp3a25 mRNA were decreased in the liver (>2-14-fold) and kidneys (>2-fold) of HFD groups which correlated with a significant reduction in midazolam metabolism (by 21- and 5-fold in hepatic and kidney microsomes, respectively, p < 0.001). HFD was associated with decreased activities of cyp2b and cyp2c subfamilies in all organs tested except in the kidneys (for tolbutamide). Other cyp450 hepatic activities were minimally or not affected by HFD. Taken together, our data suggest that substrate-dependent and tissue-dependent modulation of cyp450 metabolic capacities by early phases of T2D are observed, which could modulate drug disposition and pharmacological effects in various tissues.