Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes.
Article Details
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Klees TM, Sheffels P, Dale O, Kharasch ED
Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes.
Drug Metab Dispos. 2005 Mar;33(3):303-11. Epub 2004 Nov 22.
- PubMed ID
- 15557344 [ View in PubMed]
- Abstract
The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b(5). Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b(5) were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b(5) qualitatively and quantitatively altered alfentanil metabolism, with b(5) coexpression having a greater effect than exogenous addition. Addition or coexpression of b(5) markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Alfentanil Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Alfentanil Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Troleandomycin Cytochrome P450 3A5 Protein Humans UnknownInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAlfentanilErythromycin The serum concentration of Alfentanil can be increased when it is combined with Erythromycin. AlfentanilJosamycin The serum concentration of Alfentanil can be increased when it is combined with Josamycin. AlfentanilDirithromycin The serum concentration of Alfentanil can be increased when it is combined with Dirithromycin. AlfentanilTelithromycin The serum concentration of Alfentanil can be increased when it is combined with Telithromycin. AlfentanilSolithromycin The serum concentration of Alfentanil can be increased when it is combined with Solithromycin.