Sohn D R, Kusaka M, Ishizaki T, Shin S G, Jang I J, Shin J G, Chiba K
Division of Clinical Pharmacology, National Medical Center, Tokyo, Japan.
Clin Pharmacol Ther. 1992 Aug;52(2):160-9. doi: 10.1038/clpt.1992.125.
We studied the genetically determined hydroxylation polymorphism of S-mephenytoin in a Korean population (N = 206) and the pharmacokinetics of diazepam and demethyldiazepam after an oral 8 mg dose of diazepam administered to the nine extensive metabolizers and eight poor metabolizers recruited from the population. The log10 percentage of 4-hydroxymephenytoin excreted in the urine 8 hours after administration showed a bimodal distribution with an antimode of 0.3. The frequency of occurrence of the poor metabolizers was 12.6% in the population. In the panel study of diazepam in relation to the mephenytoin phenotype, there was a significant correlation between the oral clearance of diazepam and log10 urinary excretion of 4-hydroxymephenytoin (rs = 0.777, p less than 0.01). The plasma half-life of diazepam in the poor metabolizers was longer than that in the extensive metabolizers (mean +/- SEM, 91.0 +/- 5.6 and 59.7 +/- 5.4 hours, p less than 0.005), and the poor metabolizers had the lower clearance of diazepam than the extensive metabolizers (9.4 +/- 0.5 and 17.0 +/- 1.4 ml/min, p less than 0.001). In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01). The findings indicate that the Korean subjects have a greater incidence of poor metabolizer phenotype of mephenytoin hydroxylation compared with that reported from white subjects and that the metabolism of diazepam and demethyldiazepam is related to the genetically determined mephenytoin hydroxylation polymorphism in Korean subjects.
我们研究了韩国人群（N = 206）中由基因决定的S-美芬妥因羟基化多态性，以及对从该人群中招募的9名快代谢者和8名慢代谢者口服8 mg地西泮后地西泮和去甲基地西泮的药代动力学。给药8小时后尿中排泄的4-羟基美芬妥因的log10百分比呈双峰分布，反峰为0.3。该人群中慢代谢者的发生率为12.6%。在关于地西泮与美芬妥因表型关系的专题研究中，地西泮的口服清除率与4-羟基美芬妥因的log10尿排泄量之间存在显著相关性（rs = 0.777，p < 0.01）。慢代谢者中地西泮的血浆半衰期长于快代谢者（均值±标准误，91.0±5.6和59.7±5.4小时，p < 0.005），且慢代谢者的地西泮清除率低于快代谢者（9.4±0.5和17.0±1.4 ml/min，p < 0.001）。此外，去甲基地西泮的血浆半衰期在快代谢者（95.9±11.3小时）和慢代谢者（213.1±10.7小时）之间存在统计学显著差异（p < 0.001），且与4-羟基美芬妥因的log10尿排泄量相关（rs = -0.615，p < 0.01）。这些发现表明，与白人受试者的报告相比，韩国受试者中美芬妥因羟基化慢代谢者表型的发生率更高，并且地西泮和去甲基地西泮的代谢与韩国受试者中由基因决定的美芬妥因羟基化多态性有关。
