Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
Drug Metab Pharmacokinet. 2012;27(1):9-54. doi: 10.2133/dmpk.dmpk-11-rv-111. Epub 2011 Nov 29.
Drug lag, recently discussed extensively in Japan, can be divided into two phases: clinical development time and application review time. The former factor is still an important problem that might be improved by promoting multi-regional clinical trials and considering the results from other similar populations with Japanese, such as Koreans and Chinese. In this review, we compare the allelic or genotype frequencies of 30 relatively common functional alleles mainly between Eastern Asians and Europeans as well as among 3 major populations in Eastern Asian countries, Japan, Korea, and China, in 12 pharmacokinetics (PK)/pharmacodynamics (PD)-related genes; CYP2C9 (*2 and *3), CYP2C19 (*2, *3 and *17), 13 CYP2D6 haplotypes including *4, 5 and 10, CYP3A5 (3), UGT1A1 (28 and 6), NAT2 (5, 6 and 7), GSTM1 and GSTT1 null genotypes, SLCO1B1 521T>C, ABCG2 421C>A, and HLA-A31:01 and HLA-B58:01. In this review, differences in allele frequencies (AFs) or genotype frequencies (GFs) less than 0.1 (in the cases of highest AF (GF) ≥0.1) or less than 0.05 (in the cases of lowest AF (GF) <0.1) were regarded as similar. Between Eastern Asians and Europeans, AFs (or GFs) are regarded as being different for many alleles such as CYP2C9 (*2), CYP2C19 (*2, *3 and *17), CYP2D6 (*4 and *10), CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5*7), GSTT1 null and ABCG2 421C>A. Among the 3 Eastern Asian populations, however, only AFs of CYP2C193, CYP2D610, HLA-A31:01 and HLA-B58:01 are regarded as dissimilar. For CYP2C193, the total functional impact on CYP2C19 could be small if the frequencies of the two null alleles CYP2C192 and 3 are combined. Regarding CYP2D610, frequency difference over 0.1 is observed only between Japanese and Chinese (0.147). Although environmental factors should be considered for PK/PD differences, we could propose that among Japan, Korea, and China, genetic differences are very small for the analyzed common PK-related gene polymorphisms. On the other hand, AFs of the two HLA alleles important for cutaneous adverse drug reactions are diverse even among Eastern Asians and thus should be taken into account.
药物滞后在日本被广泛讨论，可以分为两个阶段：临床开发时间和应用审查时间。前者仍然是一个重要问题，可以通过促进多区域临床试验并考虑来自日本的其他类似人群（如韩国人和中国人）的结果来改善。在这篇综述中，我们比较了东亚人和欧洲人之间以及东亚三个主要国家（日本、韩国和中国）的 12 个药代动力学（PK）/药效学（PD）相关基因中的 30 个相对常见的功能等位基因的等位基因或基因型频率；CYP2C9（*2 和 *3）、CYP2C19（2、3 和 17）、13 个 CYP2D6 单倍型包括4、5 和10、CYP3A5（3）、UGT1A1（28 和 6）、NAT2（5、6 和 7）、GSTM1 和 GSTT1 无效基因型、SLCO1B1 521T>C、ABCG2 421C>A 和 HLA-A31:01 和 HLA-B58:01。在本综述中，等位基因频率（AF）或基因型频率（GF）差异小于 0.1（最高 AF（GF）≥0.1 的情况下）或小于 0.05（最低 AF（GF）<0.1 的情况下）被认为是相似的。在东亚人和欧洲人之间，CYP2C9（*2）、CYP2C19（*2、*3 和 *17）、CYP2D6（*4 和 *10）、CYP3A5（*3）、UGT1A1（*28 和 *6）、NAT2（*5*7）、GSTT1 无效和 ABCG2 421C>A 等许多等位基因的 AF（或 GF）被认为是不同的。然而，在东亚的 3 个人群中，只有 CYP2C193、CYP2D610、HLA-A31:01 和 HLA-B58:01 的 AF 被认为是不同的。对于 CYP2C193，如果将两个无效等位基因 CYP2C192 和 3 的频率结合起来，对 CYP2C19 的总功能影响可能很小。关于 CYP2D610，只有在日本和中国人之间观察到频率差异大于 0.1（0.147）。尽管应该考虑环境因素对 PK/PD 差异的影响，但我们可以提出，在日本、韩国和中国之间，分析的常见 PK 相关基因多态性的遗传差异非常小。另一方面，对于与皮肤不良反应相关的两种 HLA 等位基因的 AF 即使在东亚人群中也存在多样性，因此应该考虑到这一点。
