title: Panipenem does not alter the pharmacokinetics of the active metabolite of irinotecan SN-38 and inactive metabolite SN-38 glucuronide (SN-38G) in rats.
abstract: The present study has investigated the effect of panipenem, a widely used antibiotic, on the pharmacokinetics of an active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide (SN-38G) produced by uridine-diphosphate glucuronosyltransferase (UGT) 1A isoform-mediated glucuronidation in rats. Rats received a 1 h infusion with panipenem at a loading dose of 10 mg/kg and a maintenance dose of 15 mg/min/kg once a day for 5 days. When the effect of pretreatment with panipenem on glucuronidation activities of substrates for hepatic UGT1A isoforms was investigated using substrates 4-methylumbelliferone (4MU), estradiol and SN-38, the rate of 4MU glucuronide formation was significantly increased, but that of estradiol glucuronide formation was unchanged. However, the rate of SN-38G formation showed a tendency to increase. One hour after the final infusion of panipenem or saline, SN-38 (2 mg/kg) was administered intravenously in rats with or without bile duct cannulation. Pretreatment with panipenem had no effect on the plasma concentration-time curves and biliary excretion of SN-38 and SN-38G in rats with and without bile duct cannulation. There were also no significant differences in the relative extent of glucuronidation of SN-38 to SN-38G (AUC(2 h, SN-38G)/AUC(2 h, SN-38)) between panipenem-treated and untreated rats. These findings suggest that pretreatment with panipenem does not alter the pharmacokinetics of SN-38 and SN-38G, suggesting the possibility that panipenem can be used safely for cancer patients undergoing irinotecan chemotherapy.
authors.affiliation: Department of Hospital Pharmacy and Pharmacokinetics, Aichi Medical University School of Medicine, Aichi-gun, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kato
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Fumie
authors.initials: F
authors.lastname: Abe
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hotta
authors.forename: Ikuto
authors.initials: I
authors.lastname: Tsukiyama
authors.forename: Taeyuki
authors.initials: T
authors.lastname: Oshima
authors.forename: Fumio
authors.initials: F
authors.lastname: Kondo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Saito
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020719:Glucuronides / Q000493:pharmacokinetics; D000077146:Irinotecan; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013845:Thienamycins / Q000494:pharmacology*
chemical_list: D020719:Glucuronides; D013845:Thienamycins; D000077146:Irinotecan; C039536:panipenem; D002166:Camptothecin