1. ¹Departments of Anesthesiology, Legal Medicine, and Pharmaceutical Sciences, University of Tsukuba, Tsukuba
2. ²Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Naruto.

Correspondence: Shinichi Inomata, MD, Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail: inomatas@md.tsukuba.ac.jp

^†Funded by a grant from the University of Tsukuba Research Projects (to Dr Inomata).

^*Presented at the 13th World Congress of Anaesthesiologists; April 21, 2004; Paris, France.

Received 16 May 2005; Accepted 29 August 2005.

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 10^-10) was significantly lower than that of the rapid-emergence group (mean SD, 12.50 11.90 10^-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.