Use of midazolam urinary metabolic ratios for cytochrome P450 3A (CYP3A) phenotyping

Midazolam (MDZ) total clearance (Cl-T) is widely used for cytochrome P450 3 A (CYP3A) phenotyping, but requires up to eight blood samples. This study w as conducted to compare the use of midazolam Cl-T to use of a midazolam uri nary metabolic ratio for CYP3A phenotyping. Ten male and 10 female subjects received i.v. midazolam 0.025 mg/kg eight times over a 4-month period at a pproximately 2-week intervals. The first six phenotyping measures were used to estimate baseline CYP3A activity, then subjects received the moderate C PP3A inhibitor fluvoxamine 150 mg/day for the last 4 weeks (two phenotyping visits) of the study. Serial blood samples were obtained for calculation o f Cl-T. Urine was collected for 6 h following each midazolam dose. Midazola m, 1'-hydroxymidazolam (1-OHMDZ), and 4-hydroxymidazolam were measured in p lasma and urine by liquid chromatography with tandem mass spectrometry (LC/ MS/MS). Analysis of 148 samples from 20 subjects revealed a weak overall co rrelation between the urinary ratio of 1-OHMDZ/MDZ to midazolam Cl-T of r(s )= 0.372 (P = 0.0001), There was no correlation when examining either basel ine samples or fluvoxamine-inhibited samples alone (r(s)=0.101, P=0.289 and r(s)= 0.266, P = 0.123, respectively), The median (range) urinary ratio de creased significantly with fluvoxamine [219 (141-409) versus 127 (50-464); P = 0.005] and to a similar extent to the midazolam CIT (-33.6% versus -42. 4%, respectively; P > 0.05), Median urinary recovery of the i.v. midazolam dose varied between 1.4% and 53% and was significantly lower in samples col lected while patients were receiving fluvoxamine (34.3% versus 23.1%: P=0.0 004), Based on these results, although this midazolam urinary ratio was not very reflective of baseline CYP3A activity, it may be a useful indicator o f CYP3A inhibition. Pharmacogenetics 11:349-355 (C) 2001 Lippincott William s & Wilkins.