Massively parallel characterization of CYP2C9 variant enzyme activity and abundance.

CYP2C9 encodes a cytochrome P450 enzyme responsible for metabolizing up to 15% of small molecule drugs, and CYP2C9 variants can alter the safety and efficacy of these therapeutics. In particular, the anti-coagulant warfarin is prescribed to over 15 million people annually and polymorphisms in CYP2C9 can affect individual drug response and lead to an increased risk of hemorrhage. We developed click-seq, a pooled yeast-based activity assay, to test thousands of variants. Using click-seq, we measured the activity of 6,142 missense variants in yeast. We also measured the steady-state cellular abundance of 6,370 missense variants in a human cell line by using variant abundance by massively parallel sequencing (VAMP-seq). These data revealed that almost two-thirds of CYP2C9 variants showed decreased activity and that protein abundance accounted for half of the variation in CYP2C9 function. We also measured activity scores for 319 previously unannotated human variants, many of which may have clinical relevance.

INTEDE: interactome of drug-metabolizing enzymes.

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.

Drug Interactions in Space: a Cause for Concern?

PURPOSE: Crewmembers aboard the International Space Station (ISS) have free access to an increasing number of medications within medical kits. The aim of the current study was to assess the number, severity and reliability of potential drug-drug interactions (DDIs) involving those medications. METHODS: We evaluated the information obtained from clinical decision support systems. Searches for potential DDIs were applied to published lists of medications available to US astronauts in medical kits aboard the ISS. RESULTS: A total of 311 potential DDIs were identified by Lexi-Interact, of which approximately half were recognized by Micromedex as well. Major, moderate and minor interactions consisted 23.5%, 68.5% and 8.0% of entries, respectively. The reliability of 71.1% of alerts was fair. Commonly used drugs, including zolpidem and zaleplon, were involved in multiple potential interactions that were classified as major based on additive CNS depression. CONCLUSIONS: Most potential DDIs likely to be encountered in space are unestablished even in terrestrial medicine and their assignment is based on class-effects. Yet, some drug combinations may be associated with clinically-relevant consequences. Future DDI rating should be adjusted to space-related outcomes. Until that happens, it would be advisable to avoid non-established drug combinations in space when possible.

Oxidoreductases for the remediation of organic pollutants in water - a critical review.

Water contamination by various recalcitrant organic aromatic compounds is an emerging environmental issue that is increasingly attracting the attention of environmental scientists. A great majority of these recalcitrant pollutants are industrial wastes, textile dyes, pharmaceuticals, hormones, and personal care products that are discharged into wastewater. Not surprisingly, various chemical, physical, and biological strategies have been proposed and developed to remove and/or degrade these pollutants from contaminated water bodies. Biological approaches, specifically using oxidoreductase enzymes (such as peroxidases and laccases) for pollutant degradation are a relatively new and a promising research area that has potential advantages over other methods due to their higher efficiency and the ease of handling. This review focuses on the application of different classes of oxidoreductase enzymes to degrade various classes of organic pollutants. In addition to classifying these enzymes based on structural differences, the major factors that can affect their remediation ability, such as the class of peroxidases employed, pH, molecular structure of the pollutant, temperature, and the presence of redox mediators are also examined and discussed. Interestingly, a literature survey combined with our unpublished data suggests that "peroxidases" are a very heterogeneous and diverse family of enzymes and have different pH profiles, temperature optima, thermal stabilities, requirements for redox mediators, and substrate specificities as well as varying detoxification abilities. Additionally, remediation of real-life polluted samples by oxidoreductases is also highlighted as well as a critical look at current challenges and future perspectives.

Predicting unintended effects of drugs based on off-target tissue effects.

Unintended effects of drugs can be caused by various mechanisms. Conventional analysis of unintended effects has focused on the target proteins of drugs. However, an interaction with off-target tissues of a drug might be one of the unintended effect-related mechanisms. We propose two processes to predict a drug's unintended effects by off-target tissue effects: 1) identification of a drug's off-target tissue and; 2) tissue protein - symptom relation identification (tissue protein - symptom matrix). Using this method, we predicted that 1,177 (10.7%) side-effects were related to off-target tissue effects in 11,041 known side-effects. Off-target tissues and unintended effects of successful repositioning drugs were also predicted. The effectiveness of relations of the proposed tissue protein - symptom matrix were evaluated by using the literature mining method. We predicted unintended effects of drugs as well as those effect-related off-target tissues. By using our prediction, we are able to reduce drug side-effects on off-target tissues and provide a chance to identify new indications of drugs of interest.

Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs.

OBJECTIVE: To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extended-release and immediate-release oxycodone/acetaminophen fixed-dose combination analgesicsDesign. Randomized, double-blind, active- and placebo-controlled, 7-way crossover studySetting. Contract research organizationSubjects. Nondependent recreational users of prescription opioids. METHODS: Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored. RESULTS: Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax (tmax) was significantly longer (P<0.001) for intact immediate-release/extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmax for immediate-release/extended-release oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmax and area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711-0.997). CONCLUSION: Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmax and longer tmax than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.

Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

The Influence of Intestinal Tract and Probiotics on the Fate of Orally Administered Drugs.

Although the liver has long been considered as a main organ responsible for drug metabolism, the role of the gut metabolizing enzymes and the gut microflora is becoming more profoundly evident in drug metabolism, absorption and overall efficacy. This review will explore various mechanisms by which the gut-microflora influences drug pharmacokinetics including biotransformation, bioactivation, and biodegradation as well as up- or down-regulation of the epithelial transporters. The gut-luminal fluids, intestinal mucosa and gut microflora contain high concentrations of various enzymes which are responsible for the oxidation, hydrolysis and conjugation of drugs. Such metabolic reactions may lead to either drug over- or under-dosing, which impacts the drugs efficacy and safety. The processes, by which the intestinal enzymes and gut-protein transporters influence drug pharmacokinetic parameters, will be detailed. Since the intestinal microflora plays an important role in physiological, nutritional, metabolic, and immunological processes in human body, there is currently some interest in the manipulation of its composition and activity by administering probiotics. This review will also examine the capacity of probiotics to interact with resident microbial community, affecting the respective enzymes or by providing their own specific enzymatic activities that may consequently change the bioavailability and pharmacological activity of concomitantly taken drugs.

Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET.

The norepinephrine transporter (NET) transports norepinephrine from the synapse into presynaptic neurons, where norepinephrine regulates signaling pathways associated with cardiovascular effects and behavioral traits via binding to various receptors (e.g., ß2-adrenergic receptor). NET is a known target for a variety of prescription drugs, including antidepressants and psychostimulants, and may mediate off-target effects of other prescription drugs. Here, we identify prescription drugs that bind NET, using virtual ligand screening followed by experimental validation of predicted ligands. We began by constructing a comparative structural model of NET based on its alignment to the atomic structure of a prokaryotic NET homolog, the leucine transporter LeuT. The modeled binding site was validated by confirming that known NET ligands can be docked favorably compared to nonbinding molecules. We then computationally screened 6,436 drugs from the Kyoto Encyclopedia of Genes and Genomes (KEGG DRUG) against the NET model. Ten of the 18 high-scoring drugs tested experimentally were found to be NET inhibitors; five of these were chemically novel ligands of NET. These results may rationalize the efficacy of several sympathetic (tuaminoheptane) and antidepressant (tranylcypromine) drugs, as well as side effects of diabetes (phenformin) and Alzheimer's (talsaclidine) drugs. The observations highlight the utility of virtual screening against a comparative model, even when the target shares less than 30% sequence identity with its template structure and no known ligands in the primary binding site.

Down the hatch: is prescribing medication really that simple?

Drug absorption and metabolism is influenced by age, sex, pharmacogenetic variability, medical comorbidity, concurrent drug use, drug formulation, and route of administration. Drug dissolution typically begins in the stomach, but absorption occurs mainly in the small intestine. Malabsorption syndromes, previous gastrointestinal (GI) surgery, or decreased GI blood flow impair or delay the absorption of orally administered drugs. Decreased drug absorption can occur with certain gastric bypass procedures when the stomach or proximal small intestine is an important absorption site. Drugs undergoing extensive first-pass hepatic metabolism can have increased concentrations and greater systemic effects when administered directly into the jejunum. Non-oral routes of drug administration ordinarily bypass first-pass hepatic metabolism, leading to greater bioavailability and higher concentrations compared with oral administration of the same dose. Metabolic activity is variably reduced with increased age or liver disease severity, but declines in liver function cannot be quantified to determine drug metabolizing capacity.

Absence of 'over-the-counter' medicinal products in on-line prescription records: a risk factor of overlooking interactions in the elderly.

PURPOSE: To assess possible origins of harmful interactions in elderly patients arising from the current absence of information on over-the-counter (OTC) medicines in the Danish 'on-line prescription record'. METHODS: Information on current use of prescription drugs and OTC medicinal products (non-prescription drugs, herbal medicine, dietary supplements, and others) was collected by home visit interviews. The latter OTC products were not listed in an on-line prescription record that covered the previous two years. Information on interactions between OTC medicines and between OTC products and prescription drugs was obtained from the Danish National Drug Interaction Database. RESULTS: Of the 309 patients recruited (median age 75 years, interquartile range (IQR) 70-81), 229 (74%) used 568 OTC medicines not listed in the Danish 'on-line prescription record', amongst which we identified 166 potential interactions - between OTC treatments or between OTC and prescription drugs. Fifty percent of patients taking OTC medicines were exposed to potential interactions, i.e. one to three instances per patient. Twenty-five percent of patients exposed to interactions experienced interaction listed as 'Can be used with certain precautions'. CONCLUSION: The absence of information on OTC products in an on-line prescription record entails a risk of overlooking interactions in elderly patients. Such products should be included in on-line medication records to prevent adverse effects from interactions. However, online medication records are not available in all countries and as inclusion of data on OTC drugs seem not to be feasible presently. Still, it is highly recommended that the patient's drug list is reviewed on a regular basis.

Prescription drugs and mitochondrial metabolism.

Mitochondria are central to the physiology and survival of nearly all eukaryotic cells and house diverse metabolic processes including oxidative phosphorylation, reactive oxygen species buffering, metabolite synthesis/exchange, and Ca2+ sequestration. Mitochondria are phenotypically heterogeneous and this variation is essential to the complexity of physiological function among cells, tissues, and organ systems. As a consequence of mitochondrial integration with so many physiological processes, small molecules that modulate mitochondrial metabolism induce complex systemic effects. In the case of many commonly prescribed drugs, these interactions may contribute to drug therapeutic mechanisms, induce adverse drug reactions, or both. The purpose of this article is to review historical and recent advances in the understanding of the effects of prescription drugs on mitochondrial metabolism. Specific 'modes' of xenobiotic-mitochondria interactions are discussed to provide a set of qualitative models that aid in conceptualizing how the mitochondrial energy transduction system may be affected. Findings of recent in vitro high-throughput screening studies are reviewed, and a few candidate drug classes are chosen for additional brief discussion (i.e. antihyperglycemics, antidepressants, antibiotics, and antihyperlipidemics). Finally, recent improvements in pharmacokinetics models that aid in quantifying systemic effects of drug-mitochondria interactions are briefly considered.

Microphysiological systems in absorption, distribution, metabolism, and elimination sciences.

The use of microphysiological systems (MPS) to support absorption, distribution, metabolism, and elimination (ADME) sciences has grown substantially in the last decade, in part driven by regulatory demands to move away from traditional animal-based safety assessment studies and industry desires to develop methodologies to efficiently screen and characterize drugs in the development pipeline. The past decade of MPS development has yielded great user-driven technological advances with the collective fine-tuning of cell culture techniques, fluid delivery systems, materials engineering, and performance enhancing modifications. The rapid advances in MPS technology have now made it feasible to evaluate critical ADME parameters within a stand-alone organ system or through interconnected organ systems. This review surveys current MPS developed for liver, kidney, and intestinal systems as stand-alone or interconnected organ systems, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug ADME. Whereas some systems are more suitable for ADME type research than others, not all system designs were intended to meet the recently published desired performance criteria and are reported as a summary of initial proof-of-concept studies.

Personalizing medicine with clinical pharmacogenetics.

Clinical genetic testing has grown substantially over the past 30 years as the causative mutations for Mendelian diseases have been identified, particularly aided in part by the recent advances in molecular-based technologies. Importantly, the adoption of new tests and testing strategies (e.g., diagnostic confirmation, prenatal testing, and population-based carrier screening) has often been met with caution and careful consideration before clinical implementation, which facilitates the appropriate use of new genetic tests. Although the field of pharmacogenetics was established in the 1950s, clinical testing for constitutional pharmacogenetic variants implicated in interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others. This review presents some of the current opportunities and challenges with implementing clinical pharmacogenetic testing.

Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events.

UNLABELLED: Reactive metabolites generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury (DILI), but supporting data are limited. If this is true, then compounds with significant hepatic metabolism should cause more DILI than those without it. We conducted a study to examine the relationship between hepatic metabolism and DILI of prescription medications. We systematically extracted the metabolism characteristics of 207 of the most widely prescribed oral medications in the United States. Compounds with >50% hepatic metabolism were characterized as those with significant hepatic metabolism (n = 149). Hepatic adverse events of interest were alanine aminotransferase >3 times the upper limit of normal, jaundice, liver failure, liver transplantation, or fatal DILI. Compared with compounds with lesser hepatic metabolism, compounds belonging to the significant hepatic metabolism group had significantly higher frequency of alanine aminotransferase >3 times the upper limit of normal (35% versus 11%, P = 0.001), liver failure (28% versus 9%, P = 0.004), and fatal DILI (23% versus 4%, P = 0.001), but not jaundice (46% versus 35%, P = 0.2) or liver transplantation (9% versus 2%, P = 0.11). Twelve compounds with no hepatic metabolism had no reports of liver failure, liver transplantation, or fatal DILI. When the relationship between hepatic adverse events and combination of hepatic metabolism and daily dose was examined, compounds with both significant hepatic metabolism and daily dose >50 mg (n = 50) were significantly more hepatotoxic than compounds belonging to other groups. Compared with medications without biliary excretion, compounds with biliary excretion (n = 50) had significantly higher frequency of jaundice (74% versus 40%, P = 0.0001). CONCLUSION: Our study finds an important relationship between a compound's metabolism profile and reports of hepatic adverse events.

Identification and validation of novel human pregnane X receptor activators among prescribed drugs via ligand-based virtual screening.

Human pregnane X receptor (hPXR) plays a key role in regulating metabolism and clearance of endogenous and exogenous substances. Identification of novel hPXR activators among commercial drugs may aid in avoiding drug-drug interactions during coadministration. We applied ligand-based computational approaches for virtual screening of a commonly prescribed drug database (SCUT). Bayesian classification models were generated with a training set comprising 177 compounds using Fingerprints and 117 structural descriptors. A cell-based luciferase reporter assay was used for evaluation of chemical-mediated hPXR activation in HepG2 cells. All compounds were tested at 10 µM concentration with rifampicin and dimethyl sulfoxide as positive and negative controls, respectively. The Bayesian models showed specificity and overall prediction accuracy up to 0.92 and 0.69 for test set compounds. Screening the SCUT database with this model retrieved 105 hits and 17 compounds from the top 25 hits were chosen for in vitro testing. The reporter assay confirmed that nine drugs, i.e., fluticasone, nimodipine, nisoldipine, beclomethasone, finasteride, flunisolide, megestrol, secobarbital, and aminoglutethimide, were previously unidentified hPXR activators. Thus, the present study demonstrates that novel hPXR activators can be efficiently identified among U.S. Food and Drug Administration-approved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.

Network-based analysis and characterization of adverse drug-drug interactions.

Co-administration of multiple drugs may cause adverse effects, which are usually known but sometimes unknown. Package inserts of prescription drugs are supposed to contain contraindications and warnings on adverse interactions, but such information is not necessarily complete. Therefore, it is becoming more important to provide health professionals with a comprehensive view on drug-drug interactions among all the drugs in use as well as a computational method to identify potential interactions, which may also be of practical value in society. Here we extracted 1,306,565 known drug-drug interactions from all the package inserts of prescription drugs marketed in Japan. They were reduced to 45,180 interactions involving 1352 drugs (active ingredients) identified by the D numbers in the KEGG DRUG database, of which 14,441 interactions involving 735 drugs were linked to the same drug-metabolizing enzymes and/or overlapping drug targets. The interactions with overlapping targets were further classified into three types: acting on the same target, acting on different but similar targets in the same protein family, and acting on different targets belonging to the same pathway. For the rest of the extracted interaction data, we attempted to characterize interaction patterns in terms of the drug groups defined by the Anatomical Therapeutic Chemical (ATC) classification system, where the high-resolution network at the D number level is progressively reduced to a low-resolution global network. Based on this study we have developed a drug-drug interaction retrieval system in the KEGG DRUG database, which may be used for both searching against known drug-drug interactions and predicting potential interactions.

The sources and popularity of online drug information: an analysis of top search engine results and web page views.

BACKGROUND: The Internet has become a popular source of health information. However, there is little information on what drug information and which Web sites are being searched. OBJECTIVE: To investigate the sources of online information about prescription drugs by assessing the most common Web sites returned in online drug searches and to assess the comparative popularity of Web pages for particular drugs. METHODS: This was a cross-sectional study of search results for the most commonly dispensed drugs in the US (n=278 active ingredients) on 4 popular search engines: Bing, Google (both US and Canada), and Yahoo. We determined the number of times a Web site appeared as the first result. A linked retrospective analysis counted Wikipedia page hits for each of these drugs in 2008 and 2009. RESULTS: About three quarters of the first result on Google USA for both brand and generic names linked to the National Library of Medicine. In contrast, Wikipedia was the first result for approximately 80% of generic name searches on the other 3 sites. On these other sites, over two thirds of brand name searches led to industry-sponsored sites. The Wikipedia pages with the highest number of hits were mainly for opiates, benzodiazepines, antibiotics, and antidepressants. CONCLUSIONS: Wikipedia and the National Library of Medicine rank highly in online drug searches. Further, our results suggest that patients most often seek information on drugs with the potential for dependence, for stigmatized conditions, that have received media attention, and for episodic treatments. Quality improvement efforts should focus on these drugs.

Nursing role in the pharmaceutical life cycle.

Biologically active, nontherapeutic levels of pharmaceuticals have been detected in waterways and effluent. Although the vast majority of releases stem from human or animal excretion and production effluent, some come from disposal practices. Studies have demonstrated numerous links between environmental exposures from pharmaceutical compounds and their impact upon aquatic life. Nurses need to be aware of this issue since their roles in health care are expanding and considered among the most trusted. Throughout the life cycle of pharmaceuticals (design, approval/regulation, production, use, and discharge/disposal), nursing can play pivotal roles in reducing and eliminating pharmaceutical waste as well as improving public safety through decreasing poisoning and drug abuse. This article discusses the environmental impact of the pharmaceutical life cycle and what roles nurses have as clinicians, educators, advocates, and researchers.

Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3).

BACKGROUND: Transporter-mediated drug-nutrient interactions have the potential to cause serious adverse events. However, unlike drug-drug interactions, these drug-nutrient interactions receive little attention during drug development. The clinical importance of drug-nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2; SLC19A3). OBJECTIVE: In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency. METHODS: For this exploration, we took a multifaceted approach, starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors. RESULTS: Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 µM. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 µM to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR-2, particularly in vulnerable populations (e.g., individuals with alcoholism). CONCLUSIONS: Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations.