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The CYP3A4^*18 Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Department of Pharmacology and Pharmacogenomics Research Center (S.-J.L., S.S.L., H.-E.J., J.-H.S., J.-Y. R., Y.E.S., K.-H.L., W.K., J.-G.S.), Department of Clinical Pharmacology (J.-H.S., J.-G.S.), and Department of Anesthetics (Y.-J.P., C.-M.S.), Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Korea

The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4^*18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar to that of Asians, suggesting that CYP3A4^*18 would be the highest coding variant in Asians. The recombinant CYP3A4.18 protein prepared in baculovirus expression system showed 67.4% lower V_max and 1.8-fold higher K_m for midazolam 1'-hydroxylation compared with the wild type. The mean values of C_max and area under the concentration curve (AUC) in the CYP3A4^*1/^*18 and CYP3A5^*1/^*3 subjects (n = 8) were 63% and 32% higher than in CYP3A4^*1/^*1 and CYP3A5^*1/^*3 carriers (n = 8), respectively. Although the in vitro assay exhibited a significant reduction of the enzyme activity for midazolam, the in vivo differences associated with the CYP3A4^*1/^*18 tend to be low (P < 0.07 in C_max and P < 0.09 in AUC). In summary, the heterozygous CYP3A4^*1/^*18 does not appear to cause a significant change of midazolam disposition in vivo; however, the clinical relevance of CYP3A4^*18/^*18 remains to be evaluated.