Prediction of cyclosporine clearance in liver transplant recipients by the use of midazolam as a cytochrome P450 3A probe.
BACKGROUND
Interindividual differences in the kinetics of cyclosporine (INN, ciclosporin) result in part from variations in the activity of cytochrome P450 3A (CYP3A). The biotransformation of midazolam to 1'-hydroxymidazolam is also catalyzed by CYP3A. The objective of this study was to examine the usefulness of midazolam as a CYP3A probe to predict cyclosporine clearance.


METHODS
Twenty-six stable liver transplant recipients receiving immunosuppressive 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 1'-hydroxymidazolam was measured by gas chromatography-mass spectrometry. Blood concentration of cyclosporine was measured by a fluorescence polarization assay. Cyclosporine clearance was calculated as daily dose divided by trough level.


RESULTS
There were large interindividual variations in cyclosporine clearance and in midazolam metabolism. Cyclosporine blood levels correlated poorly with dose (r = -0.016). However, there was a significant correlation between cyclosporine clearance and the plasma concentration of 1'-hydroxymidazolam (r = 0.559; P < .001) or the midazolam/1'-hydroxymidazolam plasma concentration ratio (r = 0.668; P < .001).


CONCLUSIONS
Heterogeneity in CYP3A activity contributes to interpatient differences in cyclosporine dosage requirements after liver transplantation. Midazolam metabolism correlated with cyclosporine clearance, but it accounted for only about 40% of the variability in the apparent oral clearance of cyclosporine and this relationship is not tight enough to be useful in the prediction of cyclosporine dosage requirements in the clinical setting.
Villeneuve
J P
JP
Department of Medicine and Biochemistry, Centre Hospitalier Universitaire de Montréal, Hôpital Saint-Luc, Québec, Canada.
L'Ecuyer
L
L
De Maeght
S
S
Bannon
P
P
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects* / Q000378:metabolism; D011237:Predictive Value of Tests
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam