Jones D R, Gorski J C, Haehner B D, O'Mara E M, Hall S D
Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis 46202, USA.
Clin Pharmacol Ther. 1996 Oct;60(4):374-84. doi: 10.1016/S0009-9236(96)90194-0.
Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Dextromethorphan is N-demethylated in vitro to 3-methoxymorphinan by human CYP3A4/5. We examined whether the dextromethorphan/3-methoxymorphinan urinary metabolic ratio (MR) could be used as an in vivo probe of CYP3A. Urinary excretion of 3-methoxymorphinan was excretion rate-limited in extensive metabolizers of CYP2D6, which necessitated a longer urine collection, 0 to 72 hours, to obtain true MR values for CYP3A. The urine excretion of dextromethorphan and 3-methoxymorphinan was delayed in poor metabolizers of CYP2D6 but appeared to be formation rate-limited. The delayed excretion in poor metabolizers necessitated longer urine collection intervals, 0 to 11 days, to estimate the true CYP3A MR and 0 to 8 days to estimate the true CYP2D6 MR. However, a 72-hour collection in poor metabolizers was used as an index of the true dextromethorphan/3-methoxymorphinan MR. Rifampin (300 mg b.i.d. for 7 days) significantly reduced the 0- to 72-hour dextromethorphan/3-methoxymorphinan MR consistent with an 830% (+/- 1808%) induction of CYP3A activity (n = 8), whereas erythromycin (250 mg q.i.d. for 7 days) significantly increased the dextromethorphan/3-methoxymorphinan MR, corresponding to a 34% +/- 44% inhibition of activity (n = 7) in extensive metabolizers and poor metabolizers. The changes in CYP3A activity were independent of CYP2D6 phenotype and were also observed after 24- and 48-hour urine collections in extensive metabolizers and poor metabolizers. In addition, MRs reflecting CYP2D6 and CYP3A were not significantly correlated. We conclude that the commonly used antitussive dextromethorphan can be used as an in vivo marker of CYP3A and CYP2D6 activity.
右美沙芬在体内被广泛用于对多态性表达的细胞色素P450（CYP）2D6进行表型分析。右美沙芬在体外被人CYP3A4/5 N-去甲基化为3-甲氧基吗啡喃。我们研究了右美沙芬/3-甲氧基吗啡喃尿代谢比值（MR）是否可用作CYP3A的体内探针。在CYP2D6广泛代谢者中，3-甲氧基吗啡喃的尿排泄受排泄速率限制，这需要更长的尿液收集时间（0至72小时）来获取CYP3A的真实MR值。在CYP2D6慢代谢者中，右美沙芬和3-甲氧基吗啡喃的尿排泄延迟，但似乎受生成速率限制。慢代谢者中排泄延迟需要更长的尿液收集间隔时间（0至11天）来估计真实的CYP3A MR，以及0至8天来估计真实的CYP2D6 MR。然而，在慢代谢者中进行72小时的收集被用作真实右美沙芬/3-甲氧基吗啡喃MR的指标。利福平（300mg，每日两次，共7天）显著降低了0至72小时的右美沙芬/3-甲氧基吗啡喃MR，这与CYP3A活性增加830%（±1808%）一致（n = 8），而红霉素（250mg，每日四次，共7天）显著增加了右美沙芬/3-甲氧基吗啡喃MR，在广泛代谢者和慢代谢者中分别对应活性抑制34%±44%（n = 7）。CYP3A活性的变化与CYP2D6表型无关，在广泛代谢者和慢代谢者中进行24小时和48小时尿液收集后也观察到了这种变化。此外，反映CYP2D6和CYP3A的MRs无显著相关性。我们得出结论，常用的镇咳药右美沙芬可作为CYP3A和CYP2D6活性的体内标志物。
