title: Effects of non-ionic surfactants on cytochrome P450-mediated metabolism in vitro.
abstract: The purpose of the study was to investigate the impact of commonly used non-ionic surfactants on cytochrome P450 (CYP) 3A4-mediated metabolism of testosterone and the CYP2C9-mediated metabolism of diclofenac. Polysorbate 80 (PS 80), D-α-tocopheryl polyethylene glycol (1000) succinate (TPGS), sucrose laurate, Cremophor EL (CR EL), and Cremophor RH 40 (Cr RH 40) were incubated with human liver microsomes at different concentrations to determine the IC(50) of the reduced metabolism of the model substrates. Inhibitory potential in case of all tested compounds could be observed already below their critical micelle concentrations (CMC) and in concentration-dependant manner. The IC(50) of the CYP 3A4-mediated 6β-hydroxylation of testosterone has been determined as 0.40 mM (PS 80), 0.15 mM (TPGS), 0.20mM (sucrose laurate), 0.60mM (CrEL), and 0.80 mM (CrRH40). The IC(50) concerning the CYP 2C9-mediated 4-hydroxylation of diclofenac has been calculated to be 0.04 mM (PS80), 0.30 mM (TPGS), 0.07 mM (sucrose laurate), 0.03 mM (CrEL), and 0.03 mM (Cr RH 40). The results indicate that these non-ionic surfactants are in vitro inhibitors of CYP-mediated metabolism and might have the potential to modify the pharmacokinetics of co-administered drugs, which are substrates of CYP, and thereby enhance their bioavailability.
authors.affiliation: Analytical Development, Bayer Schering Pharma AG, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Christiansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Backensfeld
authors.forename: Karsten
authors.initials: K
authors.lastname: Denner
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry; D008823:Micelles; D013501:Surface-Active Agents / Q000494:pharmacology*
chemical_list: D008823:Micelles; D013501:Surface-Active Agents; D003577:Cytochrome P-450 Enzyme System