CYP3A4 drug interactions: correlation of 10 in vitro probe substrates.

Article Details

Citation

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
DrugEnzymeKindOrganismPharmacological ActionActions
ErythromycinCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Details
SalbutamolCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details
Drug Interactions
DrugsInteraction
Abemaciclib
Rosuvastatin
The metabolism of Abemaciclib can be decreased when combined with Rosuvastatin.
Abemaciclib
Tenofovir alafenamide
The metabolism of Abemaciclib can be decreased when combined with Tenofovir alafenamide.
Abemaciclib
Duvelisib
The metabolism of Abemaciclib can be decreased when combined with Duvelisib.
Abemaciclib
Idelalisib
The metabolism of Abemaciclib can be decreased when combined with Idelalisib.
Abemaciclib
Azithromycin
The metabolism of Abemaciclib can be decreased when combined with Azithromycin.
Abemaciclib
Methysergide
The metabolism of Abemaciclib can be decreased when combined with Methysergide.
Abemaciclib
Albendazole
The metabolism of Abemaciclib can be decreased when combined with Albendazole.
Abemaciclib
Doxazosin
The metabolism of Abemaciclib can be decreased when combined with Doxazosin.
Abemaciclib
Cisapride
The metabolism of Abemaciclib can be decreased when combined with Cisapride.
Abemaciclib
Norethisterone
The metabolism of Abemaciclib can be decreased when combined with Norethisterone.
Interactions
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more