title: Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants.
abstract: Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a time-dependent manner. The maximum inactivation rate constants, k(inact,max), of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The K(I) values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.
authors.affiliation: Keio University Faculty of Pharmacy.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Marie
authors.initials: M
authors.lastname: Ito
authors.forename: Saori
authors.initials: S
authors.lastname: Murase
authors.forename: Mitsue
authors.initials: M
authors.lastname: Miyazaki
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Koujirou
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
mesh_terms: D017291:Clarithromycin / Q000037:antagonists & inhibitors*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004917:Erythromycin / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D004917:Erythromycin; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; D017291:Clarithromycin