In Vivo CYP3A Activity Is Significantly Lower in Cyclosporine‐Treated as Compared With Tacrolimus‐Treated Renal Allograft Recipients

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 d...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2011-09, Vol.90 (3), p.414-422
Main Authors: Jonge, H, Loor, H, Verbeke, K, Vanrenterghem, Y, Kuypers, D R J
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Calcineurin - physiology
Calcineurin - therapeutic use
Calcineurin Inhibitors
Case-Control Studies
Cyclosporine - adverse effects
Cyclosporine - therapeutic use
Cytochrome P-450 CYP3A - blood
Cytochrome P-450 CYP3A - genetics
Cytochrome P-450 CYP3A - metabolism
Drug Interactions
Female
Genotype
Humans
Immunosuppressive Agents - adverse effects
Immunosuppressive Agents - therapeutic use
Kidney Transplantation
Liver - enzymology
Liver - metabolism
Male
Medical sciences
Midazolam - blood
Midazolam - pharmacokinetics
Pharmacology. Drug treatments
Polymorphism, Single Nucleotide
Polypharmacy
Tacrolimus - adverse effects
Tacrolimus - therapeutic use
Transplantation, Homologous
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Summary: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
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2011.130