EFFECT OF CODEINE ON GASTROINTESTINAL MOTILITY IN RELATION TO CYP2D6 PHENOTYPE

Background: Codeine is widely used as an analgesic and antitussive dru g. The analgesic effect of codeine is mediated by its metabolite morph ine, which is formed by the polymorphically expressed enzyme CYP2D6; t herefore poor metabolizers have no analgesia after administration of c odeine. Like other opiates, codeine causes a delay of gastric emptying and spastic constipation. It is not yet known whether the effect on g astrointestinal motility is mediated by codeine or its metabolite morp hine. 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 meta bolizers of sparteine with the sulfasalazine-sulfapyridine method, ass uming that no effects are observed in poor metabolizers because neglig ible amounts of morphine are formed. Results: No differences of orocec al transit times were observed between extensive metabolizers and poor metabolizers after oral placebo administration. However, after oral c odeine administration orocecal transit time was significantly prolonge d in extensive metabolizer but not poor metabolizer subjects. ALL phar macokinetic parameters of codeine showed no differences between extens ive metabolizers and poor metabolizers. The pharmacokinetic parameters (mean +/- SD) of the metabolite morphine were significantly different between extensive metabolizer and poor metabolizer subjects (peak ser um concentration, 13.9 +/- 10.5 versus 0.68 +/- 0.15 pmol/ml; area und er 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 mu mol). Conclusions: Because the orocecal transit time prolongation after codeine administration was observed on ly in extensive metabolizers, the effect of codeine on gastrointestina l motility, like the analgesia, is mediated by its metabolite morphine .