In addition to drug metabolizing enzymes, drug transporters play an important role in pharmacodynamic (PD) and pharmacokinetic (PK) outcomes in anti-cancer drug therapy. Among the various drug transporters, ABC transporters such as MDR1, MRP1, MRP2 and BCRP are well known multiple anti-cancer drug resistance proteins. Individualized anti-cancer drug therapy based on the expression levels of these ABC transporters in cancer tissues has already been applied in the surgical treatment of glioblastoma and anaplastic astrocymota. OATP1B1 (organic anion transporting polypeptide 1B1), an influx transporter expressed at the basolateral membranes of hepatocytes, is also involved in the PK profile of irinotecan. Recent studies suggest that the screening of UGT1A1 variants (e.g., ^*28 and ^*60) and SLCO1B1 variants (especially for ^*15) is useful in irinotecan chemotherapy to avoid unpredicted severe toxicity.

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In a meta-analysis, 21% of patients treated with clopidogrel, an antagonist for P2Y12 receptors, achieved low or no ex vivo inhibition of ADP-induced platelet aggregation, which may be caused by CYP2C19 polymorphism. However, it remains unresolved whether or not the polymorphism of CYP2C19 would affect the pharmacokinetics of the active metabolite of clopidogrel (AM) and the pharmacodynamics of antiplatelet effects to the AM. Therefore, in this study, we investigated whether the polymorphism of CYP2C19 would affect the formation of the AM and the antiplatelet effects to the AM in healthy subjects. In single dose study, 300mg clopidogrel was orally given to 47 subjects. The mean AUC and Cmax of the AM differed significantly (P<0.05) between the extensive metabolizers (EMs, n=18) and the intermediate metabolizers (IMs, n=20), as well as between EMs and the poor metabolizers (PMs, n=9). Moreover, the pharmacokinetic parameters of the AM correlated well with ADP-induced platelet aggregation and the vasodilator-stimulated phosphoprotein phosphorylation ratio. In another study, 75mg clopidogrel was orally given to 10 different subjects for 7 days. The non- or lower responsiveness to clopidogrel in the PMs could not be improved by repeated administration. The CYP2C19 pharmacogenomic status is a determinant for the formation of the AM and antiplatelet effects in healthy subjects.

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Warfarin is the mainstay of anticoagulation therapy, worldwide. Its clinical use, however, is complicated by the fact that it has a narrow therapeutic index with potential bleeding complications. The dosage requirement of warfarin to produce therapeutic anticoagulation varies widely among patients. Recently genetic factors such as the CYP2C9 and VKORC1 genes have been demonstrated to be determinants of warfarin response. CYP2C9 is the enzyme primarily responsible for the metabolic clearance of the S-enantiomer of warfarin. VKOR is the target protein of warfarin which recycles the reduced form of vitamin K, an essential cofactor in the formation of the vitamin K-dependent clotting factors. There is strong evidence to support an association between these genetic variants and therapeutic doses of warfarin. On the basis of these observations, the Food and Drug Administration (FDA) approved a labeling change for warfarin that includes the genetic information of VKORC1 and CYP2C9 as factors influencing inter-individual variability in warfarin dosing. The package insert as of August 2007 states that “lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes.” The FDA also approved clinical tests for these genetic variants. However, at present, a validated dosing algorithm, evidence of the clinical utility of genotyping and a reliable economic analysis are not availabie to recommend routine CYP2C9 and VKORC1 testing in every patient before the initiation of warfarin. The results of several randomized prospective controlled trials conducted to test the impact of genotype-guided warfarin dosing in Caucasian and Asian patients are shown in this review.

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Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. Despite the availability of the new biological agents such as TNF-blocking agents, methotrexate (MTX) remains as the primary agent for the treatment of RA due to the low and broad experience with its use. The efficacy and adverse drug reactions of MTX are variable among patients, and this is partially contributed in genetic difference of drug-metabolizing enzymes, transporters, and receptors In this review, we described MTX pharmacogenetics that was related to a large interindividual variation on efficacy and adverse drug reactions in RA patients, including MTX transporter pharmacogenetics, MTX glutamation pharmacogenetics, folate pathway pharmacogenetics, and adenosine pathway pharmacogenetics. We also described the clinical implications between their pharmacogenetics and clinical outcomes (efficacy and/or adverse drug reactions of MTX)

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The two major factors associated with the development of peptic ulcer diseases are H. pylori infection and NSAID (non-steroidal anti-inflammatory drug). It has been made clear that various genetic polymorphisms are involved in the pathogenesis of peptic ulcer diseases, such as polymorphisms in the immune responses to H. pylori infection, those in virulence factors of H. pylori, those in the metabolism of NSAIDs including aspirin, and those in the mucosal defense system. There are also various polymorphisms in the therapeutics of peptic ulcer disease. How to apply this genetic information to clinical practice is the important theme.

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Multinational clinical trials are considered to be one of the effective means for solving many issues including the “drug lag” problem facing regulatory authorities and pharmaceutical companies in Japan. Multinational Asian clinical trials are of particular interest for the Japanese pharmaceutical community and have attracted attention recently due to the advantages such trials can offer, such as cross-regional data sharing and enrolling sufficient patients. However, only a few reports on multinational Asian clinical trials are available. Considering this background, this article provides a detailed analysis of the current multinational clinical trial status focusing on the Asian region and proposes a basis for development strategies for clinical trials in Japan such as study design streamlining and country and region selections. We compiled clinical trial data and created a secondary database to analyze the current multinational clinical trial status involving Asian countries by extracting information from ClinicalTrials.gov (http://clinicaltrials.gov/), a website hosted by the U.S. National Institutes of Health, through the National Library of Medicine in collaboration with the U.S. Food and Drug Administration. As a result of this analysis, it was found that multinational Asian clinical trials have been conducted with a wide variation in involvement of countries and regions. Also the trends of characteristic involvement of different countries and regions, vary with the study designs and therapeutic areas. We therefore conclude that clinical trial development strategies including the selection of countries and regions need to reflect the individual positions of studies in the clinical context as well as the characteristics of compounds. Also, in the drastically changing climate of multinational clinical trials, it is crucial to keep updating the latest trend of multinational clinical trials in order to shape good development strategies.

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The aim of this study was to organize a laboratory exercise to study the relationship between CYP2C19 genotype and phenotype measured by omeprazole metabolism. In the Department of Clinical Pharmacology, Hirosaki University School of Medicine, 5th year medical students participated in the laboratory exercise of a 2-day course after they gave written informed consent. They were phenotyped by measuring plasma omeprazole and 5-hydoxyomeprazole concentrations after administering 2 tablets of 20 mg omeprazole, and also genotyped with a PCR-RFLP method to identify defective mutation alleles for CYP2C19, CYP2C19^*2 and CYP2C19^*3. The procedure of CYP2C19 genotyping and phenotyping required almost one day, but most 5th year medical students were successfully able to demonstrate the relationship between their genotype and phenotype. Although some PMs showed atypical metabolic ratios of omeprazole to 5-hydroxyomeprazole probably due to a few sampling method, our laboratory exercise led to reliable and impressive results for medical students.

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