可待因对与CYP2D6表型相关的胃肠动力的影响。

Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype.

作者信息

Mikus G, Trausch B, Rodewald C, Hofmann U, Richter K, Gramatté T, Eichelbaum M

机构信息

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

出版信息

Clin Pharmacol Ther. 1997 Apr;61(4):459-66. doi: 10.1016/S0009-9236(97)90196-X.

DOI:10.1016/S0009-9236(97)90196-X

PMID:9129563

Abstract

BACKGROUND

Codeine is widely used as an analgesic and antitussive drug. The analgesic effect of codeine is mediated by its metabolite morphine, which is formed by the polymorphically expressed enzyme CYP2D6; therefore poor metabolizers have no analgesia after administration of codeine. Like other opiates, codeine causes a delay of gastric emptying and spastic constipation. It is not yet known whether the effect on gastrointestinal motility is mediated by codeine or its metabolite morphine.

METHODS

To test the hypothesis that the metabolite morphine is responsible for the effects of codeine on gastrointestinal motility, a randomized, double-blind, two-way crossover study was performed. The orocecal transit time was studied in five extensive and five poor metabolizers of sparteine with the sulfasalazine-sulfapyridine method, assuming that no effects are observed in poor metabolizers because negligible amounts of morphine are formed.

RESULTS

No differences of orocecal transit times were observed between extensive metabolizers and poor metabolizers after oral placebo administration. However, after oral codeine administration orocecal transit time was significantly prolonged in extensive metabolizer but not poor metabolizer subjects. All pharmacokinetic parameters of codeine showed no differences between extensive metabolizers and poor metabolizers. The pharmacokinetic parameters (mean +/- SD) of the metabolite morphine were significantly different between extensive metabolizer and poor metabolizer subjects (peak serum concentration, 13.9 +/- 10.5 versus 0.68 +/- 0.15 pmol/ml; area under the serum concentration-time curve, 27.8 +/- 16.0 versus 1.9 +/- 0.7 hr.pmol/ml; total amount of morphine excreted in urine, 0.160 +/- 0.036 versus 0.015 +/- 0.007 mumol).

CONCLUSIONS

Because the orocecal transit time prolongation after codeine administration was observed only in extensive metabolizers, the effect of codeine on gastrointestinal motility, like the analgesia, is mediated by its metabolite morphine.

摘要

背景

可待因作为一种镇痛和止咳药物被广泛使用。可待因的镇痛作用由其代谢产物吗啡介导，吗啡由多态性表达的细胞色素P450 2D6酶形成；因此，慢代谢者服用可待因后无镇痛作用。与其他阿片类药物一样，可待因会导致胃排空延迟和痉挛性便秘。目前尚不清楚对胃肠动力的影响是由可待因还是其代谢产物吗啡介导的。

方法

为了验证代谢产物吗啡是可待因对胃肠动力产生影响的原因这一假设，进行了一项随机、双盲、双向交叉研究。采用柳氮磺胺吡啶法对5名司巴丁快代谢者和5名慢代谢者的口盲肠转运时间进行了研究，假定慢代谢者中未观察到影响是因为形成的吗啡量可忽略不计。

结果

口服安慰剂后，快代谢者和慢代谢者的口盲肠转运时间无差异。然而，口服可待因后，快代谢者的口盲肠转运时间显著延长，而慢代谢者则未延长。可待因的所有药代动力学参数在快代谢者和慢代谢者之间均无差异。代谢产物吗啡的药代动力学参数（平均值±标准差）在快代谢者和慢代谢者之间有显著差异（血清峰值浓度，13.9±10.5对0.68±0.15 pmol/ml；血清浓度-时间曲线下面积，27.8±16.0对1.9±0.7 hr.pmol/ml；尿中吗啡排泄总量，0.160±0.036对0.015±0.007 μmol）。