细胞色素P450 2C19基因型影响地西泮的药代动力学及全身麻醉后的苏醒。

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.

作者信息

Inomata Shinichi, Nagashima Atsushi, Itagaki Fumio, Homma Masato, Nishimura Masuhiro, Osaka Yoshiko, Okuyama Kazuhiko, Tanaka Einosuke, Nakamura Takako, Kohda Yukinao, Naito Shinsaku, Miyabe Masayuki, Toyooka Hidenori

机构信息

Departments of Anesthesiology, Legal Medicine, and Pharmaceutical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.

出版信息

Clin Pharmacol Ther. 2005 Dec;78(6):647-55. doi: 10.1016/j.clpt.2005.08.020.

DOI:10.1016/j.clpt.2005.08.020

PMID:16338280

Abstract

OBJECTIVES

Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics.

METHODS

Sixty-three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction-restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia.

RESULTS

CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24-hour period (AUC(0-24)) (2088 +/- 378 ng/mL.h(-1), P = .0259), lower clearance of diazepam (0.049 +/- 0.009 L.h(-1).kg(-1), P = .0287), and longer emergence time (median, 18 minutes; 25th-75th percentile range, 13-21 minutes; P < .001) in comparison with subjects in the EM group (AUC(0-24), 1412 +/- 312 ng/mL; clearance, 0.074 +/- 0.018 L.h(-1).kg(-1); and emergence time, 10 minutes, 8-12 minutes [median and 25th-75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th-75th percentile range, 9-20 minutes; P < .001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence <20 minutes, slow emergence >20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow-emergence group (mean +/- SD, 4.80 +/- 3.99 x10(-10)) was significantly lower than that of the rapid-emergence group (mean +/- SD, 12.50 +/- 11.90 x10(-10)) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601).

CONCLUSION

We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow-emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid-emergence group.

摘要

目的

地西泮被广泛用于缓解患者的术前焦虑。本研究的目的是调查CYP2C19基因多态性的影响以及血液中CYP3A4信使核糖核酸（mRNA）含量对全身麻醉恢复和地西泮药代动力学的影响。

方法

根据CYP2C19基因多态性的聚合酶链反应-限制性片段长度多态性分析，将63例日本患者分为以下3个基因型（表型）组：无变异，*1/*1（广泛代谢型[EM]）；1个变异，*1/2或1/*3（中间代谢型[IM]）；2个变异，*2/*2、*2/3或3/*3（慢代谢型[PM]）。我们评估了这些多态性以及淋巴细胞中CYP3A4 mRNA含量对患者全身麻醉恢复的影响。

结果

对63名受试者的CYP2C19基因分型分析表明，分别有32%、46%和22%的受试者被分为EM组、IM组和PM组。与EM组受试者相比（AUC(0-24)，1412±312 ng/mL；清除率，0.074±0.018 L·h-1·kg-1；苏醒时间，10分钟，8-12分钟[中位数和第25-75百分位数范围]），PM组受试者在24小时内代表地西泮浓度的曲线下面积（AUC(0-24)）更大（2088±378 ng/mL·h-1，P = 0.0259），地西泮清除率更低（0.049±0.009 L·h-1·kg-1，P = 0.0287），苏醒时间更长（中位数，18分钟；第25-75百分位数范围，13-21分钟；P < 0.001）。与EM组相比，IM组的苏醒时间也更长（中位数，13分钟；第25-75百分位数范围，9-20分钟；P < 0.001），且该参数的变异性更大。两组（苏醒快<20分钟，苏醒慢>20分钟）之间CYP2C19基因型的分布有显著差异（P = 0.0148）。苏醒慢组中CYP3A4 mRNA水平的平均值（平均值±标准差，4.80±3.99×10-10）显著低于苏醒快组（平均值±标准差，12.50±11.90×10-10）（P = 0.0315）。然而，苏醒时间与CYP3A4 mRNA水平之间无显著相关性（r = 0.239，P = 0.0601）。