双氢可待因：一种用于人类多态性CYP2D6的新型阿片类底物。

Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans.

作者信息

Fromm M F, Hofmann U, Griese E U, Mikus G

机构信息

Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.

出版信息

Clin Pharmacol Ther. 1995 Oct;58(4):374-82. doi: 10.1016/0009-9236(95)90049-7.

DOI:10.1016/0009-9236(95)90049-7

PMID:7586928

Abstract

BACKGROUND

The opioid dihydrocodeine (DHC) is frequently used as an analgesic and antitussive agent. However, until now there have been no detailed data on dihydrocodeine metabolism in humans. We therefore investigated pathways that contribute to elimination of dihydrocodeine, and we tested the hypothesis that dihydrocodeine O-demethylation to dihydromorphine (DHM) is catalyzed by the polymorphic CYP2D6.

METHODS

A single oral dose of dihydrocodeine was administered to six extensive (metabolic ratio [MR] < or = 1), two intermediate (1 < MR < 20) and six poor metabolizers (MR > or = 20) of sparteine/debrisoquin. Serum concentrations of dihydrocodeine and dihydromorphine were measured up to 25 hours, and urinary excretion of conjugated and unconjugated dihydrocodeine, dihydromorphine, and nordihydrocodeine were determined.

RESULTS

There were no differences in the pharmacokinetics of dihydrocodeine between extensive and poor metabolizers. However, the area under the serum concentration-time curve (AUC), partial metabolic clearance, and total urinary recovery of dihydromorphine were significantly lower in poor metabolizers (10.3 +/- 6.1 nmol.hr/L; 7.0 +/- 4.1 ml/min; 1.3% +/- 0.9% of dose) compared with extensive metabolizers (75.5 +/- 42.9 nmol.hr/L; 49.7 +/- 29.9 ml/min; 8.9% +/- 6.2%; p < 0.01). There was a strong correlation between the AUCDHC/AUCDHM ratio and the urinary metabolic ratio of sparteine (rS = 0.89, p = 0.001). No significant differences between extensive and poor metabolizers were detected in urine for conjugated dihydrocodeine (extensive metabolizers, 27.7% of dose; poor metabolizers, 31.5%), unconjugated dihydrocodeine (extensive metabolizers, 31.1%; poor metabolizers, 31.1%), conjugated nordihydrocodeine (extensive metabolizers, 6.3%; poor metabolizers, 5.4%), or unconjugated nordihydrocodeine (extensive metabolizers, 15.8%; poor metabolizers, 19.5%).

CONCLUSIONS

Dihydrocodeine O-demethylation to dihydromorphine is impaired in poor metabolizers of sparteine. The main urinary metabolites after administration of dihydrocodeine are the parent compound and its conjugates in extensive and poor metabolizers.

摘要

背景

阿片类药物双氢可待因（DHC）常被用作镇痛药和止咳药。然而，迄今为止，尚无关于双氢可待因在人体内代谢的详细数据。因此，我们研究了双氢可待因的消除途径，并检验了双氢可待因经O-去甲基化生成二氢吗啡（DHM）是由多态性CYP2D6催化的这一假说。

方法

对6名司巴丁/异喹胍代谢快者（代谢比[MR]≤1）、2名代谢中等者（1＜MR＜20）和6名代谢慢者（MR≥20）单次口服双氢可待因。在25小时内测定双氢可待因和二氢吗啡的血清浓度，并测定结合型和非结合型双氢可待因、二氢吗啡及去甲双氢可待因的尿排泄量。

结果

代谢快者和代谢慢者之间双氢可待因的药代动力学无差异。然而，与代谢快者相比，代谢慢者中二氢吗啡的血清浓度-时间曲线下面积（AUC）、部分代谢清除率和尿总回收率显著降低（分别为10.3±6.1nmol·hr/L；7.0±4.1ml/min；剂量的1.3%±0.9%）（代谢快者分别为75.5±42.9nmol·hr/L；49.7±29.9ml/min；8.9%±6.2%；p＜0.01）。双氢可待因AUC与二氢吗啡AUC之比与司巴丁的尿代谢比之间存在强相关性（rS = 0.89，p = 0.001）。在尿中，结合型双氢可待因（代谢快者为剂量的27.7%；代谢慢者为31.5%）、非结合型双氢可待因（代谢快者为31.1%；代谢慢者为31.1%）、结合型去甲双氢可待因（代谢快者为6.3%；代谢慢者为5.4%）或非结合型去甲双氢可待因（代谢快者为15.8%；代谢慢者为19.5%）在代谢快者和代谢慢者之间未检测到显著差异。