CYP3A4 drug interactions: correlation of 10 in vitro probe substrates.
Article Details
- CitationCopy to clipboard
Kenworthy KE, Bloomer JC, Clarke SE, Houston JB
CYP3A4 drug interactions: correlation of 10 in vitro probe substrates.
Br J Clin Pharmacol. 1999 Nov;48(5):716-27.
- PubMed ID
- 10594474 [ View in PubMed]
- Abstract
AIMS: Many substrates of cytochrome P450 (CYP) 3A4 are used for in vitro investigations of drug metabolism and potential drug-drug interactions. The aim of the present study was to determine the relationship between 10 commonly used CYP3A4 probes using modifiers with a range of inhibitory potency. METHODS: The effects of 34 compounds on CYP3A4-mediated metabolism were investigated in a recombinant CYP3A4 expression system. Inhibition of erythromycin, dextromethorphan and diazepam N-demethylation, testosterone 6beta-hydroxylation, midazolam 1-hydroxylation, triazolam 4-hydroxylation, nifedipine oxidation, cyclosporin oxidation, terfenadine C-hydroxylation and N-dealkylation and benzyloxyresorufin O-dealkylation was evaluated at the apparent Km or S50 (for substrates showing sigmoidicity) value for each substrate and at an inhibitor concentration of 30 microM. RESULTS: While all CYP3A4 probe substrates demonstrate some degree of similarity, examination of the coefficients of determination, together with difference and cluster analysis highlighted that seven substrates can be categorized into two distinct substrate groups. Erythromycin, cyclosporin and testosterone form the most closely related group and dextromethorphan, diazepam, midazolam and triazolam form a second group. Terfenadine can be equally well placed in either group, while nifedipine shows a distinctly different relationship. Benzyloxyresorufin shows the weakest correlation with all the other CYP3A4 probes. Modifiers that caused negligible inhibition or potent inhibition are generally comparable in all assays, however, the greatest variability is apparent with compounds causing, on average, intermediate inhibition. Modifiers of this type may cause substantial inhibition, no effect or even activation depending on the substrate employed. CONCLUSIONS: It is recommended that multiple CYP3A4 probes, representing each substrate group, are used for the in vitro assessment of CYP3A4-mediated drug interactions.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Albuterol Cytochrome P450 3A4 Protein Humans UnknownInhibitorDetails Erythromycin Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAbemaciclibRosuvastatin The metabolism of Abemaciclib can be decreased when combined with Rosuvastatin. AbemaciclibDuvelisib The metabolism of Abemaciclib can be decreased when combined with Duvelisib. AbemaciclibIdelalisib The metabolism of Abemaciclib can be decreased when combined with Idelalisib. AbemaciclibAzithromycin The metabolism of Abemaciclib can be decreased when combined with Azithromycin. AbemaciclibMethysergide The metabolism of Abemaciclib can be decreased when combined with Methysergide.