Differences in Drug Pharmacokinetics Between East Asians and Caucasians and the Role of Genetic Polymorphisms

Abstract

Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both genetic and environmental factors can lead to these differences among ethnic groups. The International Conference on Harmonization (ICH) published a guidance to facilitate the registration of drugs among ICH regions (European Union, Japan, the United States) by recommending a framework for evaluating the impact of ethnic factors on a drug's effect, as well as its efficacy and safety at a particular dosage and dosage regimen. This review focuses on the pharmacokinetic differences between East Asians and Caucasians. Differences in metabolism between East Asians and Caucasians are common, especially in the activity of several phase I enzymes such as CYP2D6 and the CYP2C subfamily. Before drug therapy, identification of either the genotype and/or the phenotype for these enzymes may be of therapeutic value, particularly for drugs with a narrow therapeutic index. Furthermore, these differences are relevant for international drug approval when regulatory agencies must decide if they accept results from clinical trials performed in other parts of the world.

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…With regards to the CYP2C9*3 allele in these regions, the frequency of the derived C allele was higher in the European populations (average HGDP-CEPH ¼ 9% and Canadian samples ¼ 4%) than in East Asians (CEPH ¼ 4% and Canadian samples ¼ 1%). These figures are in general agreement with those reported by Kim et al, 37 who found that the frequency of the CYP2C9*3 variant was 8% in Europeans and 2% in East Asians. With respect to the distribution of these polymorphisms in other population groups, it is interesting to note that, whereas the frequency of the CYP2C9*2 allele is lower in Central/ South Asian populations than in Europe (average HGDP-CEPH in Central/South Asia¼7%, and Canadian South Asian sample ¼ 5%), the opposite is true for the CYP2C9*3 allele (average HGDP-CEPH in Central/South Asia ¼ 10%, and Canadian South Asian sample ¼ 12%).…”

“…15,16,17 The results from genotyping the HGDP-CEPH and Canadian samples are in accordance with literature on the allele frequency of the CYP2C9*2 and *3 variants among European and East Asian populations. The CYP2C9*2 allele has been most extensively studied among European populations in which it appears at a frequency of approximately 10%, 37 which is comparable to our findings of frequencies between 13% and 17% in the HGDP-CEPH and Canadian European samples, respectively. Previous research has indicated that the CYP2C9*2 variant is extremely rare if not absent in East Asian populations.…”

“…Previous research has indicated that the CYP2C9*2 variant is extremely rare if not absent in East Asian populations. 37 With the exception of the Yakut (2%), we observed that the derived T allele was absent in all East Asian populations from the HGDP-CEPH sample and appeared at a frequency of 0.5% among the Canadian East Asians. With regards to the CYP2C9*3 allele in these regions, the frequency of the derived C allele was higher in the European populations (average HGDP-CEPH ¼ 9% and Canadian samples ¼ 4%) than in East Asians (CEPH ¼ 4% and Canadian samples ¼ 1%).…”

“…These findings are also in agreement with studies indicating that, on average, warfarin dose requirements among East Asian individuals are lower than in African and European subjects. 3,37 The average frequency of the derived T allele in European populations was 51% in the HGDP-CEPH samples and 38% in the sample of Canadians of European ancestry. These values are in the middle of those observed among the African and East Asian populations and also reflect current population-based trends in warfarin dosing.…”

Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

“…Of the genes responsible for the metabolism and transport of anticancer drugs using the WES data, we focused on the genes encoding cytochrome P450 isoforms (CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6) (Bell et al, 2015;Chen and Goldstein, 2009;Crews et al, 2012;Jin et al, 2005;Kim et al, 2004;Kiyotani et al, 2013;Takimoto et al, 2013;Tamaki et al, 2011;Xie et al, 2003), thiopurine methyltransferase (TPMT) (Chouchana et al, 2014), N-acetyltransferase 2 (NAT2) (Sim et al, 2014), UDP glucuronosyl transferase family 1 member A1 (UGT1A1) (Cheng et al, 2014;Sugatani, 2013), catechol-O-methyltransferase (COMT) (Zubieta et al, 2003), ATP-binding cassette subfamily B member 1 (ABCB1) (Bell et al, 2015;Frederiks et al, 2015), and cytidine deaminase (CDA) (Sugiyama et al, 2007(Sugiyama et al, , 2009, in the present study (Table 2) because the variants of these genes were previously described to affect drug response in Japanese populations (Kurose et al, 2012).…”