Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
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Amundsen R, Asberg A, Ohm IK, Christensen H
Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Drug Metab Dispos. 2012 Apr;40(4):655-61. doi: 10.1124/dmd.111.043018. Epub 2011 Dec 28.
- PubMed ID
- 22205779 [ View in PubMed]
- Abstract
Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 muM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Cyclosporine Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareTacrolimusPhenytoin The serum concentration of Tacrolimus can be decreased when it is combined with Phenytoin. TacrolimusFosphenytoin The serum concentration of Tacrolimus can be decreased when it is combined with Fosphenytoin.