title: Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.
abstract: While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D017291:Clarithromycin / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism*; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology*; D004917:Erythromycin / Q000378:metabolism; D015248:Gemfibrozil / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000378:metabolism*
chemical_list: D065687:Cytochrome P-450 CYP2C8 Inhibitors; D020719:Glucuronides; D000960:Hypolipidemic Agents; D045162:Thiazolidinediones; D004917:Erythromycin; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D014453:Glucuronosyltransferase; D017291:Clarithromycin; D015248:Gemfibrozil; D000077205:Pioglitazone
keywords: Acyl-glucuronide; CYP2C8; Gemfibrozil; Mechanism-based inhibition; Pioglitazone