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Introduction: Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lower cholesterol synthesis in patients with hypercholesterolemia. Increased statin exposure is an important risk factor for skeletal muscle toxicity. Potent inhibitors of cytochrome P450 (CYP) 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin, and atorvastatin. Fluvastatin is metabolized by CYP2C9, whereas pravastatin, rosuvastatin, and pitavastatin are unaffected by inhibition by either CYP. Statins also have different affinities for membrane transporters involved in processes such as intestinal absorption, hepatic absorption, biliary excretion, and renal excretion., Areas Covered: In this review, the pharmacokinetic aspects of drug-drug interactions with statins and genetic polymorphisms of CYPs and drug transporters involved in the pharmacokinetics of statins are discussed., Expert Opinion: Understanding the mechanisms underlying statin interactions can help minimize drug interactions and reduce the adverse side effects caused by statins. Since recent studies have shown the involvement of drug transporters such as OATP and BCRP as well as CYPs in statin pharmacokinetics, further clinical studies focusing on the drug transporters are necessary. The establishment of biomarkers based on novel mechanisms, such as the leakage of microRNAs into the peripheral blood associated with the muscle toxicity, is important for the early detection of statin side effects.

The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 μg sulfasalazine, 250 μg rosuvastatin, 300 μg glibenclamide, 1200 μg celiprolol, and 600 μg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups., Methods: The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used., Results: On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA., Conclusion: Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination.

Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.

Aims: To develop a novel warfarin-dosing algorithm based on a previous population pharmacokinetic/pharmacodynamic (PK/PD) model with Bayesian forecasting to facilitate warfarin therapy., Materials & Methods: Using information on CYP2C9 and VKORC1 genotypes, S-warfarin level, dose and international normalized ratio (INR) of prothrombin time, individual PK (apparent clearance of S-warfarin [CLs]) and PD (concentration resulting in 50% of E(max) [EC(50)]) parameters were determined by Bayesian forecasting for 45 Japanese patients. Maintenance doses were described by multiple linear regression using individually estimated PK/PD parameters and INR values. The validity of the model and a comparison with other dosing methods were evaluated by bootstrap resampling and a cross-validation method., Results: The plasma concentration of S-warfarin and INR were accurately predicted from individual PK/PD parameters. The following final regression model for maintenance dose was obtained; maintenance dose = 11.2 x CLs + 0.91 x EC(50) + 2.36 x INR - 9.67, giving a strong correlation between actual and predicted maintenance doses (r(2) = 0.944). Bootstrap resampling and cross-validation showed robustness and a superior predictive performance compared with other dosing methods. On the other hand, the predictability without actual measurements (S-warfarin and INR values) and Bayesian inference was comparable to other dosing methods., Conclusion: A novel algorithm, based on the population PK/PD model combined with Bayesian forecasting, gave precise predictions of maintenance dose, leading to individualized warfarin therapy.

Intra- and inter-ethnic differences in pharmacokinetic and pharmacodynamic profiles of clinically relevant drugs are important issues not only for scenes of appropriate drug use in clinical settings but also for those of the drug development. Pharmacogenomics is extremely useful for understanding these racial differences. In this presentation, I will introduce pharmacogenomic concepts (e.g., single nucleotide polymorphisms (SNPs) and haplotype) for interpretation of racial differences in some drugs; pharmacogenomics of drug transporters such as OATP1B1 (organic anion transporting-polypeptide 1B1) and OCT1 (organic cation transporter 1) in pravastatin, metformin, and rosuvastatin will be discussed as model drugs.

Drug metabolizing enzymes and transporters are increasingly recognized as key determinants of the inter-individual variability in pharmacokinetic (PK) and pharmacodynamic (PD) outcomes of clinically important drugs. To date, most studies investigating this variability have focused on polymorphisms (e.g. SNPs) in the genes encoding metabolic enzymes and transporters; however, it has recently been reported that the expression of some of these genes is under the control of epigenetic mechanisms. The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolizing enzymes and transporter genes.

Objective: To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9., Methods: Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset (n = 166), fully carboxylated plasma normal prothrombin levels (NPT) were also measured. Genotyping for seven CYP2C9 (CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement., Results: The relationship between NPT and Cu(S) indicated Japanese are more susceptible to inhibition of NPT production by S-warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients (5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype-matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (*2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage., Conclusions: Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.

To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1* 6/* 28 and SLCO1B1* 15/* 15 genotypes. A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m2) on days 1, 8 and 15 in combination with docetaxel (60 mg/m2) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1* 6/* 28 and SLCO1B1* 15/* 15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs. The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic ( UGT1A1* 6/* 28) and transport ( SLCO1B1* 15/* 15) capabilities. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the impact of CYP2C19 polymorphism on the extent of the interaction and on the pharmacokinetics and pharmacodynamics of ticlopidine.Homozygous (hmEMs) and heterozygous extensive metabolizers (htEMs), and poor metabolizers (PMs, n=6 each) took an oral dose (20 mg) of omeprazole. After a 1-week washout period, each subject received ticlopidine (200 mg) for 8 days, and ticlopidine pharmacokinetics were studied on days 1 and 7. On day 8, omeprazole was given again and its kinetic disposition was compared with that in the first dose. ADP-induced platelet aggregation was measured as a pharmacodynamic index.In contrast to the PMs, whose mean kinetic parameters were not altered by the repeated dosings of ticlopidine, an eight- to 10-fold increase in the mean AUC ratio of omeprazole to 5-hydroxyomeprazole was observed in both the EM groups. No significant intergenotypic differences in the pharmacokinetic parameters of ticlopidine were observed, although the accumulation ratio tended to be greater in hmEMs than in PMs (2.4±0.2 versus 1.7±0.2). A significantly positive correlation (P=0.031) was observed between the individual percent inhibition of platelet aggregation and AUC0-24 of ticlopidine regardless of the CYP2C19 polymorphism.Ticlopidine is a potent inhibitor for CYP2C19 and may be associated with the phenocopy when CYPC19 substrates are co-administered to EMs. Whether and to what extent CYP2C19 would be involved in the metabolism of ticlopidine remain unanswered from the present in-vivo study. [ABSTRACT FROM AUTHOR]

Abstract: Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3′-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64±4.02 versus 9.75±6.58 and 0.64±0.75 versus 1.48±1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy. [Copyright &y& Elsevier]