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-hydroxyquinidine from quinidine is catalyzed almost exclusively by CYP3A4, In vivo this 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 of 3-hydroxyquinidine with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Descriptive analyses of the outcome of various biomarker reactions were performed. Methods: Forty-two healthy, young male volunteers participated in an open study consisting of two identical test periods separated by a 12- to 14-week washout period. In each period biomarker reactions of CYP1A2 (caffeine), CYP2C9 (tolbutamide), CYP2C19 (mephenytoin), CYP2D6 (sparteine), CYP3A4 (urinary excretion of 6 beta-hydroxycortisol), as well as the pharmacokinetics of quinidine after a 200-mg single oral dose of quinidine sulfate were studied. 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 of 3-hydroxyquinidine, the intraindividual coefficient of variation for CYP3A4 activity was 18%, whereas the interindividual activity varied fourfold. The formation clearance of 3-hydroxyquinidine did not correlate with the outcome of indexes for activities of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 or the 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 oral dose of 200 mg quinidine sulfate may represent a useful index of CYP3A4 activity in vivo.