A urine metabolic ratio of dextromethorphan and 3-methoxymorphinan as a probe for CYP3A activity and prediction of cyclosporine clearance in healthy volunteers

Dextromethorphan (DM) is metabolized in the body to dextrophan (DT) and 3-m ethoxymorphinan (3-MM) by cytochrome P450 (CYP) 2D6 and 3A4, respectively, and cyclosporine (CsA) is a known substrate of CYP3A4. We attempted to dete rmine if the urine metabolic ratio of DM:3-MM at various time intervals dur ing 24 hours is predictive of CsA clearance in 11 healthy volunteers. Each subject took DM 30 mg orally, and serial urine samples were collected at 0- 4, and 4-24, and 0-24 hours. Subjects then were randomly assigned to receiv e either oral microemulsion CsA 5 mg/kg or intravenous CsA 1.5 mg/kg in a c rossover fashion in a two-sequence pharmacokinetic study with a wash-out pe riod of at least 7 days. A total of 17 blood samples were collected from ea ch subject in the CsA pharmacokinetic study over 24 hours. Urinary DM, DT, and 3-MM were quantified by high-performance liquid chromatography (HPLC) w ith a fluorescence detector, and blood CsA concentrations were analyzed by HPLC with ultraviolet detection. All subjects were extensive metabolizers o f CYP2D6 as determined by metabolic ratios of DM:DT (mean +/- SD 0.0255 +/- 0.048). There was no correlation between CYP2D6 and CYP3A4 (p=0.38). The m etabolic ratios of DM:3-MM in any urine samples during the 24-hour collecti on period did not predict CsA pharmacokinetics, although the 0-24 hour samp le had an unexpected positive correlation with CsA clearance (r(2) = 0.38, p<0.0001). The correlation was similar for metabolic ratios of DM:3-MM with intravenous CsA clearance (r(2) = 0.5, p<0.0001). Metabolic ratios of DM:3 -MM based on 24-hour cumulative urine collection did not appear to have cli nical utility in predicting CYP3A activity measured by CsA clearance.