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In Vivo CYP3A Activity Is Significantly Lower in Cyclosporine‐Treated as Compared With Tacrolimus‐Treated Renal Allograft Recipients
Author(s) -
Jonge H,
Loor H,
Verbeke K,
Vanrenterghem Y,
Kuypers D R J
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.130
Subject(s) - tacrolimus , calcineurin , cyp3a , medicine , in vivo , pharmacology , context (archaeology) , midazolam , clinical pharmacology , drug interaction , pharmacokinetics , regimen , drug , transplantation , biology , metabolism , paleontology , microbiology and biotechnology , cytochrome p450 , sedation
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. Clinical Pharmacology & Therapeutics (2011) 90 3, 414–422. doi: 10.1038/clpt.2011.130