Quinidine as a probe for CYP3A4 activity: Intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6

Background: In vitro studies have shown that the formation of 3-hydroxyquin idine from quinidine is catalyzed almost exclusively by CYP3A4, In vivo thi s result has been supported in various interaction studies, and the use of this reaction as an in vivo biomarker reaction of CYP3A4 activity has been suggested, We studied the possible correlation of the formation clearance o f 3-hydroxyquinidine with probe-based assays for CYP1A2, CYP2C9, CYP2C19, a nd CYP2D6. Descriptive analyses of the outcome of various biomarker reactio ns were performed. Methods: Forty-two healthy, young male volunteers participated in an open s tudy consisting of two identical test periods separated by a 12- to 14-week washout period. In each period biomarker reactions of CYP1A2 (caffeine), C YP2C9 (tolbutamide), CYP2C19 (mephenytoin), CYP2D6 (sparteine), CYP3A4 (uri nary excretion of 6 beta-hydroxycortisol), as well as the pharmacokinetics of quinidine after a 200-mg single oral dose of quinidine sulfate were stud ied. Results: The median formation clearance of 3-hydroxyquinidine were 2.40 and 2.33 L/h in the two test periods. As measured by the formation clearance o f 3-hydroxyquinidine, the intraindividual coefficient of variation for CYP3 A4 activity was 18%, whereas the interindividual activity varied fourfold. The formation clearance of 3-hydroxyquinidine did not correlate with the ou tcome of indexes for activities of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 or th e urinary excretion of 6 beta-hydroxycortisol, The formation clearance of 3 -hydroxyquinidine correlated well to point values of 3-hydroxyquinidine to quinidine ratios in plasma and urine. Conclusion: The formation clearance of 3-hydroxyquinidine after a single or al dose of 200 mg quinidine sulfate may represent a useful index of CYP3A4 activity in vivo.