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Statin-associated muscle symptoms (SAMS) can lead to statin nonadherence. This paper aims to develop a pharmacological SAMS risk stratification (PSAMS-RS) score using a previously developed PSAMS phenotyping algorithm that distinguishes objective vs. nocebo SAMS using electronic health record (EHR) data. Using our PSAMS phenotyping algorithm, SAMS cases and controls were identified from Minnesota Fairview EHR, with the statin user cohort divided into derivation (January 1, 2010, to December 31, 2018) and validation (January 1, 2019, to December 31, 2020) cohorts. A Least Absolute Shrinkage and Selection Operator regression model was applied to identify significant features for PSAMS. PSAMS-RS scores were calculated and the clinical utility of stratifying PSAMS risk was assessed by comparing hazard ratios (HRs) between fourth vs. first score quartiles. PSAMS cases were identified in 1.9% (310/16,128) of the derivation and 1.5% (64/4,182) of the validation cohorts. Sixteen out of 38 clinical features were determined to be significant predictors for PSAMS risk. Patients within the fourth quartile of the PSAMS scores had an over sevenfold (HR: 7.1, 95% confidence interval (CI): 4.03-12.45, derivation cohort) or sixfold (HR: 6.1, 95% CI: 2.15-17.45, validation cohort) higher hazard of developing PSAMS vs. those in their respective first quartile. The PSAMS-RS score is a simple tool to stratify patients' risk of developing PSAMS after statin initiation which could inform clinician-guided pre-emptive measures to prevent PSAMS-related statin nonadherence., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.

Fenofibrate belongs to the group of hypolipidemic fibrates that act as activators of the peroxisome proliferator-activated receptor-α (PPARα), which is a regulator of bile acid synthesis, metabolism, and transport. The present study aimed at evaluating the effects of fenofibrate on the circulating bile acid profile in humans. A study population of 200 healthy individuals comprising both genders completed a 3-week intervention with fenofibrate, and 17 bile acid species were measured in serum samples drawn before and after fenofibrate treatment. Fenofibrate caused significant reductions in levels of chenodeoxycholic (CDCA) (-26.4%), ursodeoxycholic (UDCA) (-30.5%), lithocholic (LCA) (-18.4%), deoxycholic (DCA) (-22.3%), and hyodeoxycholic (HDCA) (-19.2%) acids. A gender-related difference was observed in the responses of various bile acids, and the total bile acid concentration was significantly reduced only in men (-18.6%), whereas it remained almost unchanged in women (+0.36%). This difference suggests that fenofibrate would be more efficient at reducing bile acid toxicity in men than in women in cholestatic liver diseases.

Southeast Asians known as the Hmong have a high prevalence of tuberculosis and select cancers. The slow acetylation (SA) phenotype for N-acetyltransferase 2 (NAT2) has been associated with toxicity from the anti-tuberculosis drug, isoniazid and in increased risk of select cancers. Previous research indicates a 74.5% prevalence of SA in Hmong which differs from other Asian populations including the Japanese and Thai (range: 7%-45%). Given this contrast, the purpose of this study was to confirm or refute this unexpected predominance of the SA phenotype in Hmong. Unrelated, Minnesota Hmong between 18 and 65 years of age consented and participated by ingesting caffeine as the probe for NAT2. A urinary caffeine metabolic ratio AFMU/1X (<0.6) was used to classify subjects as slow acetylators. Among 51 analysable samples provided by 61 enrollees (27 male, 33 female, 1 sex unknown, age 30+/-11 years [mean+/-SD]) there were 47 (92.2%) slow and 4 (7.8%) rapid acetylators. The prevalence of the SA phenotype (92.2%) from this study exceeds the 74.5% (p<0.02 by chi-square test) previously noted in Minnesota Hmong (n=98). The predominance of the SA phenotype within Minnesota Hmong is confirmed. Further studies evaluating this unexpected prevalence, its genetic basis and potential clinical relevance to drug toxicity and disease are warranted., (Copyright 2006 John Wiley & Sons, Ltd.)

Polymorphisms of N-acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 +/- 11 years), analysis of 50 urine-DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population.

Recognition of the existence of circadian variation in exacerbation of cardiovascular disease may have relevance to clinical use of cardioactive agents. Physiologic rational for the chronobiology of cardiac disease exists and can provide a basis on which to examine the efficacy of agents to manage cardiac disease. The use of 24-hour ambulatory blood pressure monitoring (ABPM) devices have advanced our ability to describe the interplay of chronobiologic rhythms and pharmacodynamic response to antihypertensive medications. This review summarizes the studies evaluating the use of various antihypertensive medications in the context of using 24-hour blood pressure monitoring devices. The studies are described in an attempt to increase awareness of chronobiology and potential implications of designing chronotherapeutic regimens.

Pharmacogenetics can be an important determinant of pharmacologic response. To learn more about interpopulation differences in drug metabolism between ethnically diverse populations of subjects cared for by an International Clinic, a study was conducted to describe the prevalence of fast or slow acetylators of N-acetyltransferase (NAT2) in a population of Hmong residing in Minnesota. Ninety-eight healthy Hmong refugees from Laos volunteered to take caffeine as an oral probe drug to establish acetylator phenotype. Participants were classified as either rapid or slow acetylators based on the urinary molar ratio of select metabolites of caffeine. Assignment of phenotype was based on results from analysis of urine collected subsequent to ingestion of caffeine. The ratio of 5-acetylamino-6-formylamino-3-methyluracil (AFMU) to the combined products of the 7-demethylation pathway of paraxanthine (AFMU, 1-methylxanthine (1X), and 1-methylurate (1U)] formed the basis for this determination. A probit plot of the data collected in our subjects qualified a metabolic ratio of 0.34 as an acceptable cut point for phenotype assignment. Participants with an AFMU/(AFMU + 1X + 1U) ratio of < 0.34 were classified as slow acetylators and all others as rapid acetylators. Analysis of the data suggested a bimodal distribution with an excess (74.5%) of slow acetylators in the population. The predominance of slow acetylators found in the Hmong contrast with the prevalence of slow acetylators seen in other ethnic groups. These findings may have important clinical implications given the large number of Hmong treated each year in our International Clinic and the increasing use of medications metabolized by NAT2 in this population.

Isosorbide dinitrate is one of the most commonly prescribed medications for the treatment of ischemic heart disease. It has been demonstrated to be ineffective relative to placebo when taken inappropriately. This study objectively documents the magnitude and nature of compliance in 68 ambulatory patients who were prescribed isosorbide dinitrate three times a day. Each patient received a 9-week supply of medication in a vial equipped with a computerized monitor (MEMS-4 cap; APREX Corporation, Fremont, CA) and were informed as to the purpose of the study. Of the patients, 74% were classified into the low and 16% into the high compliance category, defined as compliant < 70% and > or = 85% of study days, respectively. The mean (+/- SD) percent days in which isosorbide dinitrate was taken three times was 66% (+/- 29), and the mean number of days in which it was taken three times with a 10-hour "nitrate free period" was 53% (+/- 31). It is concluded that the magnitude of noncompliance in patients prescribed isosorbide dinitrate three times daily is substantial (74%). The nature of this noncompliance is often due to failure to observe a 10- to 12-hour nitrate free period. Given the need to take isosorbide dinitrate appropriately and given the demonstrated magnitude of noncompliance, physicians should take these factors into consideration when selecting this agent for the management of coronary artery disease relative to other pharmacologic options.

Genetic polymorphism of the P450IID6 (CYP2D6) enzyme system can be an important component of the variability in response to drug therapy. Interpopulation differences in the prevalence of deficiencies of drug-metabolizing enzymes may be clinically important in the selection and dosage of drug therapies for patients. Since 1980, the State of Minnesota has had more than a 1000% increase in population of Hmong refugees from Laos. The Hmong are frequently treated in our institution's international clinic with virtually no systematically acquired knowledge about the ability of this relatively ethnically pure population to metabolize commonly used Western medications. To further our knowledge of drug metabolism in this population, we identified the prevalence of the poor metabolizer phenotype for CYP2D6 in a sample population of Hmong subjects and compared this prevalence to that in a sample population of white subjects. Urine collected after ingestion of dextromethorphan in 237 healthy Hmong and 280 healthy white volunteers was analyzed by HPLC. Based on probit plots of the metabolic ratios (dextro-methorphan/dextrorphan), 8.9% of Hmong subjects and 6.1% of white subjects were assigned the poor metabolizer phenotype (difference not significant). Weak associations were found between body surface area and metabolic ratio for both Hmong and white men and between smoking status and metabolic ratio for white subjects only. We conclude that the prevalence of poor metabolizers for the CYP2D6 enzyme system is similar between Hmong subjects and white subjects residing in Minnesota and that an antimode of 0.3 for metabolic ratio appears to be reasonable for the populations studied.