Can oral midazolam predict oral cyclosporine disposition?
Effective cyclosporine therapy is confounded by large interindividual differences in oral bioavailability and a narrow therapeutic window. Because cytochrome P450 (CYP) 3A-mediated first-pass metabolism contributes to this unpredictable bioavailability, an in vivo oral CYP3A phenotyping probe could be a valuable tool in optimizing cyclosporine therapy. Based on similarities in the metabolic kinetics of cyclosporine and midazolam by the liver and intestinal mucosa, we evaluated whether midazolam oral clearance would predict cyclosporine oral clearance when the two drugs were administered to 20 medically stable kidney transplant recipients. Despite earlier findings in liver transplant recipients who displayed a strong correlation between the systemic clearances of midazolam and cyclosporine, there was a weak correlation between their oral clearances in the current group of subjects (r(s)=0.50, P=0.03). Differing extents of intestinal first-pass metabolic extraction between the two drugs, inhibition of midazolam metabolism by cyclosporine at the level of the intestine, and/or P-glycoprotein-mediated intestinal efflux of cyclosporine (but not midazolam) may account for this poor correlation. We conclude that although oral midazolam is unlikely to be clinically useful as a probe for cyclosporine disposition, its utility in the prediction of other orally administered CYP3A substrates cannot be out ruled.
Paine
M F
MF
Department of Pharmaceutics, University of Washington, Seattle, WA, USA. mpaine@med.unc.edu
Davis
C L
CL
Shen
D D
DD
Marsh
C L
CL
Raisys
V A
VA
Thummel
K E
KE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014151:Anti-Anxiety Agents; 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