Prediction of cyclosporine clearance in liver transplant recipients by theuse of midazolam as a cytochrome P450 3A probe

Background: Interindividual differences in the kinetics of cyclosporine (IN N, ciclosporin) result in part from variations in the activity of cytochrom e P450 3A (CYP3A). The biotransformation of midazolam to I'-hydroxymidazola m is also catalyzed by CYP3A, The objective of this study was to examine th e usefulness of midazolam as a CYP3A probe to predict cyclosporine clearanc e. Methods: Twenty-six stable liver transplant recipients receiving immunosupp ressive therapy with oral cyclosporine (Neoral) were studied. Midazolam (0. 015 mg/kg) was administered intravenously and a blood sample was obtained 1 hour later, The plasma concentration of midazolam and I'-hydroxymidazolam was measured by gas chromatography-mass spectrometry, Blood concentration o f cyclosporine was measured by a fluorescence polarization assay. Cyclospor ine clearance was calculated as daily dose divided by trough level. Results: There were large interindividual variations in cyclosporine cleara nce and in midazolam metabolism, Cyclosporine blood levels correlated poorl y with dose (r = -0.016), However, there was a significant correlation betw een cyclosporine clearance and the plasma concentration of I'-hydroxymidazo lam (r = 0.559; P < .001) or the midazolam/1'-hydroxymidazolam plasma conce ntration ratio (r = 0.668; P < .001). Conclusion: Heterogeneity in CYP3A activity contributes to interpatient dif ferences in cyclosporine dosage requirements after liver transplantation. M idazolam metabolism correlated with cyclosporine clearance, but it accounte d for only about 40% of the variability in the apparent oral clearance of c yclosporine and this relationship is not tight enough to be useful in the p rediction of cyclosporine dosage: requirements in the clinical setting.