Exploring the impact of CYP2D6 and UGT2B7 gene-drug interactions, and CYP-mediated DDI on oxycodone and oxymorphone pharmacokinetics using physiologically-based pharmacokinetic modeling and simulation.

Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.

Pharmacogenetic Testing in a 70-Year-Old Woman with Polypharmacy and Multiple Comorbidities: A Case Report.

BACKGROUND Comorbidities and polypharmacy are difficult to manage, as polypharmacy hinders identification and prevention of medication-related problems. Risk for adverse drug events (ADEs) can be minimized through pharmacogenomic (PGx) testing and related therapeutic adjustments. CASE REPORT A 70-year-old woman with comorbidities and medications enrolled in the Program of All-inclusive Care for the Elderly presented with left lower extremity (LLE) pain, generalized weakness, and major depressive disorder. The provider requested a medication safety review, where the clinical pharmacist-recommended PGx testing given the LLE pain and weakness while taking a statin and inconsistent INR readings taking warfarin. The pharmacist recommended switching atorvastatin to pravastatin to minimize the risk for statin-associated ADEs due to CYP3A4 inhibition and switching fluoxetine to citalopram due to uncontrolled depression/anxiety and to mitigate drug-drug interactions with carvedilol to reduce the risk of orthostatic hypotension. Recommendations were accepted and upon follow-up the patient reported minor LLE pain and improved wellbeing on citalopram. Following PGx testing, the patient had decreased function at SLCO1B1 and was an intermediate metabolizer for CYP2C9 and CYP2D6. This case demonstrates how preemptive PGx testing would have identified drug-gene interactions (DGIs) at the time of prescribing and reduced the risk of statin-associated muscular symptoms, highlighting the utility of panel-based PGx testing in older adults at high risk for ADEs and/or therapy failure. CONCLUSIONS Decreased function at SLCO1B1 increases exposure to statins, leading to statin-induced myalgias, as displayed in this case. PGx testing can help identify DGIs, choose optimal therapies in medically complex older adults, and minimize ADE risk.

Multidrug Interactions: Why Do They Occur and How to Handle?

A nonoptimized medication therapy (NOMT) event is an iatrogenic hazard or incident associated with medications and is a leading cause of death, serious injury, and illness. NOMT events are often related to multidrug interactions in patients with polypharmacy. In these patients, NOMT events can be avoided by using advanced clinical decision support systems and clinical interventions such as separating the time of administration of certain drugs during the day. At the individual level, medication reconciliation is a first logical step for reducing adverse side effects. Then, intersubject variability in drug response should be considered to optimize patient drug regimens. Furthermore, patient pharmacogenomic status information can help ensure appropriateness of drug therapy. However, in patients with polypharmacy, such information is most valuable when combined with phenoconversion probability. At a population level, the virtual addition of drugs to various drug regimens and the use of a medication risk score can help predict the risk of NOMT events. This review outlines some of the mechanisms behind multidrug interactions and their association with drug safety and NOMTs, polypharmacy and its impact on patient outcomes, the value of pharmacogenomics, and an assessment of simulation studies and the virtual addition of drugs to a drug regimen using real-world data.

Quantifying Anticholinergic Burden and Sedative Load in Older Adults with Polypharmacy: A Systematic Review of Risk Scales and Models.

BACKGROUND: Patients taking medication with high anticholinergic and sedative properties are at increased risk of experiencing poor cognitive and physical outcomes. Therefore, precise quantification of the cumulative burden of their drug regimen is advisable. There is no agreement regarding which scale to use to simultaneously quantify the burden associated with medications. OBJECTIVES: The objective of this review was to assess the strengths and limitations of available tools to quantify medication-related anticholinergic burden and sedative load in older adults. We discuss specific limitations and agreements between currently available scales and models and propose a comprehensive table combining drugs categorized as high, moderate, low, or no anticholinergic or sedative activity as excerpted from the selected studies. METHODS: A targeted search was carried out using the National Library of Medicine through PubMed using medical subject heading terms and text words around the following search terms: (anticholinergic OR sedative) AND (load OR burden OR scale) for studies published between 1 January 1945 and 5 June 2021. In addition, the following databases were searched using the same terms: MEDLINE-EBSCO, APA PsycInfo, CINAHL Plus, Cochrane Library, Scopus, OAIster, OVID-MEDLINE, Web of Science, and Google Scholar. Screening by titles was followed by an abstract and full-text review. After blind evaluation, agreement between reviewers was reached to establish drug characteristics and categories. RESULTS: After 3163 articles were identified, 13 were included: 11 assigned risk scores to anticholinergic drugs and two to sedative drugs. Considerable variability between anticholinergic scales was observed; scales included between 27 and 548 drugs. We generated a comprehensive table combining the anticholinergic and sedative activities of drugs evaluated and proposed a categorization of these drugs based on available scientific and clinical evidence. Our table combines information about 642 drugs and categorizes 44, 25, 99, and 474 drugs as high, moderate, low, or no anticholinergic and sedative activity, respectively. CONCLUSIONS: Variability and inconsistency exists among scales used to categorize drugs with anticholinergic or sedative burden. In this review, we provide a comprehensive table that proposes a new categorization of these drugs. A longitudinal study will be required to validate the new proposed anticholinergic and sedative burden catalog in an evidence-based manner.

Classification and Assessment of Medication Risk in the Elderly (CARE): Use of a Medication Risk Score to Inform Patients' Readmission Likelihood after Hospital Discharge.

Existing risk tools that identify patients at high risk of medication-related iatrogenesis are not sufficient to holistically evaluate a patient's entire medication regimen. This study used a novel medication risk score (MRS) which holistically evaluates medication regimens and provides actionable solutions. The main purpose of this study was to quantify adults ≥ 65 years with a high medication risk burden using the MRS and secondarily, appraise MRS association with hospital readmission. This retrospective cohort study included all consecutive patients in a 6-month period aged 65 years and older, admitted for at least 48 h, and prescribed at least five medications upon discharge. Out of 3017 patients screened, 1386 met all criteria. The primary outcome was the proportion of patients with a score of ≥20 and the secondary outcome was the 30-day readmission rate. In the overall population, 17% of patients had an MRS ≥ 20. For patients discharged home, there was a 19% readmission rate for a score ≥ 20 and 11% for <20 (p = 0.009). A score of ;≥20 was associated with a 1.8-fold increased risk of readmission in patients discharged home. Only 7% of patients met these criteria, which can help direct future use of the MRS at patients with the highest risk of medication-related iatrogenesis.

Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity.

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.

Development and Characterization of Rice Husk and Recycled Polypropylene Composite Filaments for 3D Printing.

Nowadays the use of natural fiber composites has gained significant interest due to their low density, high availability, and low cost. The present study explores the development of sustainable 3D printing filaments based on rice husk (RH), an agricultural residue, and recycled polypropylene (rPP) and the influence of fiber weight ratio on physical, thermal, mechanical, and morphological properties of 3D printing parts. Thermogravimetric analysis revealed that the composite's degradation process started earlier than for the neat rPP due to the lignocellulosic fiber components. Mechanical tests showed that tensile strength increased when using a raster angle of 0° than specimens printed at 90°, due to the weaker inter-layer bonding compared to in-layer. Furthermore, inter layer bonding tensile strength was similar for all tested materials. Scanning electron microscope (SEM) images revealed the limited interaction between the untreated fiber and matrix, which led to reduced tensile properties. However, during the printing process, composites presented lower warping than printed neat rPP. Thus, 3D printable ecofriendly natural fiber composite filaments with low density and low cost can be developed and used for 3D printing applications, contributing to reduce the impact of plastic and agricultural waste.

Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy.

Over the last century, the process of choosing medications to treat certain diseases has evolved significantly [...].

Illustrative and historic cases of phenoconversion.

Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy.

Reusability of filtering facepiece respirators after decontamination through drying and germicidal UV irradiation.

INTRODUCTION: During pandemics, such as the SARS-CoV-2, filtering facepiece respirators plays an essential role in protecting healthcare personnel. The recycling of respirators is possible in case of critical shortage, but it raises the question of the effectiveness of decontamination as well as the performance of the reused respirators. METHOD: Disposable respirators were subjected to ultraviolet germicidal irradiation (UVGI) treatment at single or successive doses of 60 mJ/cm2 after a short drying cycle (30 min, 70°C). The germicidal efficacy of this treatment was tested by spiking respirators with two staphylococcal bacteriophages (vB_HSa_2002 and P66 phages). The respirator performance was investigated by the following parameters: particle penetration (NaCl aerosol, 10-300 nm), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry and mechanical tensile tests. RESULTS: No viable phage particles were recovered from any of the respirators after decontamination (log reduction in virus titre >3), and no reduction in chemical or physical properties (SEM, particle penetrations <5%-6%) were observed. Increasing the UVGI dose 10-fold led to chemical alterations of the respirator filtration media (FTIR) but did not affect the physical properties (particle penetration), which was unaltered even at 3000 mJ/cm2 (50 cycles). When respirators had been used by healthcare workers and undergone decontamination, they had particle penetration significantly greater than never donned respirators. CONCLUSION: This decontamination procedure is an attractive method for respirators in case of shortages during a SARS pandemic. A successful implementation requires a careful design and particle penetration performance control tests over the successive reuse cycles.

Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice.

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.

Risk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy.

Determination of the risk-benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.

Detection of Lung Tumor Progression in Mice by Ultrasound Imaging.

With ~1.6 million victims per year, lung cancer contributes tremendously to the worldwide burden of cancer. Lung cancer is partly driven by genetic alterations in oncogenes such as the KRAS oncogene, which constitutes ~25% of lung cancer cases. The difficulty in therapeutically targeting KRAS-driven lung cancer partly stems from having poor models that can mimic the progression of the disease in the lab. We describe a method that permits the relative quantification of primary KRAS lung tumors in a Cre-inducible LSL-KRAS G12D mouse model via ultrasound imaging. This method relies on brightness (B)-mode acquisition of the lung parenchyma. Tumors that are initially formed in this model are visualized as B-lines and can be quantified by counting the number of B-lines present in the acquired images. These would represent the relative tumor number formed on the surface of the mouse lung. As the formed tumors develop with time, they are perceived as deep clefts within the lung parenchyma. Since the circumference of the formed tumor is well-defined, calculating the relative tumor volume is achieved by measuring the length and width of the tumor and applying them in the formula used for tumor caliper measurements. Ultrasound imaging is a non-invasive, fast and user-friendly technique that is often used for tumor quantifications in mice. Although artifacts may appear when obtaining ultrasound images, it has been shown that this imaging technique is more advantageous for tumor quantifications in mice compared to other imaging techniques such as computed tomography (CT) imaging and bioluminescence imaging (BLI). Researchers can investigate novel therapeutic targets using this technique by comparing lung tumor initiation and progression between different groups of mice.

Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

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.

A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum.

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.

Modulation of CYP450 Activities in Patients With Type 2 Diabetes.

We conducted a comprehensive in vivo study evaluating the influence of type 2 diabetes (T2D) on major cytochrome P450 (CYP450) activities. These activities were assessed in 38 T2D and 35 non-T2D subjects after a single oral administration of a cocktail of probe drugs: 100 mg caffeine (CYP1A2), 100 mg bupropion (CYP2B6), 250 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan (CYP2D6), 2 mg midazolam (CYP3As), and 250 mg chlorzoxazone (alone; CYP2E1). Mean metabolic activity for CYP2C19, CYP2B6, and CYP3A was decreased in subjects with T2D by about 46%, 45%, and 38% (P < 0.01), respectively. CYP1A2 and CYP2C9 activities seemed slightly increased in subjects with diabetes, and no difference was observed for CYP2D6 or CYP2E1 activities. Several covariables, such as inflammatory markers (interleukin (IL)-1ß, IL-6, gamma interferon, and tumor necrosis factor alpha), genotypes, and diabetes-related and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform-specific manner.

Development and validation of probe drug cocktails for the characterization of CYP450-mediated metabolism by human heart microsomes.

1. The objective of our study was to develop and validate a cocktail approach to allow the simultaneous characterization of various CYP450-mediated oxidations by human heart microsomes for nine probe drug substrates, namely, 7-ethoxyresorufin, bupropion, repaglinide, tolbutamide, bufuralol, chlorzoxazone, ebastine, midazolam and dodecanoic acid. 2. The first validation step was conducted using recombinant human CYP450 isoenzymes by comparing activity measured for each probe drug as a function of (1) buffer used, (2) selectivity towards specific isoenzymes and (3) drug interactions between probes. Activity was all measured by validated LC-MSMS methods. 3. Two cocktails were then constituted with seven of the nine drugs and subjected to kinetic validation. Finally, all probe drugs were incubated with human heart microsomes prepared from ventricular tissues obtained from 12 patients undergoing cardiac transplantation. 4. Validated cocktail #1 including bupropion, chlorzoxazone, ebastine and midazolam was used to characterize CYP2B6-, 2E1-, 2J2- and 3A5-mediated metabolism in human hearts. 5. Cocktail #2 which includes bufuralol, 7-ethoxyresorufin and repaglinide failed the validation step. Substrates in cocktail #2 as well as tolbutamide and dodecanoic acid had to be incubated separately because of their physico-chemical characteristics (solubility and ionization) or drug interactions. 6. Activity in HHM was the highest towards ebastine, chlorzoxazone and tolbutamide.

Effects of a Series of Acidic Drugs on L-Lactic Acid Transport by the Monocarboxylate Transporters MCT1 and MCT4.

BACKGROUND: Drug-induced myopathy is a serious side effect that often requires removal of a medication from a drug regimen. For most drugs, the underlying mechanism of drug-induced myopathy remains unclear. Monocarboxylate transporters (MCTs) mediate L-lactic acid transport, and inhibition of MCTs may potentially lead to perturbation of L-lactic acid accumulation and muscular disorders. Therefore, we hypothesized that L-lactic acid transport may be involved in the development of drug-induced myopathy. The aim of this study was to assess the inhibitory potential of 24 acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 and MCT4, respectively. METHODS: The influx transport of L-lactic acid was minimally inhibited by all drugs tested. The efflux transport was next examined: loratadine (IC50: 10 and 61 µM) and atorvastatin (IC50: 78 and 41 µM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively. Acidic drugs including fluvastatin, cerivastatin, simvastatin acid, lovastatin acid, irbesartan and losartan exhibited weak inhibitory potency on L-lactic acid efflux. RESULTS: Our results suggest that some acidic drugs, such as loratadine and atorvastatin, can inhibit the efflux transport of L-lactic acid. CONCLUSION: This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders.