title: In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients.
abstract: In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 ± 73 vs. 354 ± 102 ml/min, P = 0.022) and 31% (479 ± 190 vs. 688 ± 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients.
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: de Jonge
authors.forename: H
authors.initials: H
authors.lastname: de Loor
authors.forename: K
authors.initials: K
authors.lastname: Verbeke
authors.forename: Y
authors.initials: Y
authors.lastname: Vanrenterghem
authors.forename: D R J
authors.initials: DR
authors.lastname: Kuypers
mesh_terms: D000328:Adult; D019703:Calcineurin / Q000502:physiology / Q000627:therapeutic use; D065095:Calcineurin Inhibitors; D016022:Case-Control Studies; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D019338:Polypharmacy; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*; D014184:Transplantation, Homologous
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D019703:Calcineurin; D008874:Midazolam; D016559:Tacrolimus