title: Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats.
abstract: The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan, on the pharmacokinetics of diltiazem (DTZ), a typical probe of cytochrome P450 (CYP) 3A, were examined in rats. The simultaneous addition of GBE to small intestine and liver microsomes inhibited the formation of N-demethyl DTZ (MA), an active metabolite of DTZ produced by CYP3A, in a concentration-dependent manner, with an IC(50) of about 50 and 182 microg/ml, respectively. This inhibition appeared to be caused, at least in part, by a mechanism-based inhibition. Both the rate of formation of MA and total amount of CYP in intestinal or hepatic microsomes after a single oral pretreatment with GBE (20 mg/kg) decreased transiently. The pretreatment significantly decreased the terminal elimination rate constant and increased the mean residence time, after intravenous administration of DTZ (3 mg/kg). Furthermore, it significantly increased the area under the concentration-time curve and absolute bioavailability after oral administration of DTZ (30 mg/kg). These results indicated that the concomitant use of GBE in rats increased the bioavailability of DTZ by inhibiting both intestinal and hepatic metabolism, at least in part, via a mechanism-based inhibition for CYP3A.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. ohnishi@mb.kyoto-phu.ac.jp
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ohnishi
authors.forename: Mayako
authors.initials: M
authors.lastname: Kusuhara
authors.forename: Mutsunobu
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuroda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Soga
authors.forename: Fumi
authors.initials: F
authors.lastname: Nishikawa
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Koishi
authors.forename: Masato
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hori
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Ohta
authors.forename: Koji
authors.initials: K
authors.lastname: Takara
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Yokoyama
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D015786:Cytochromes b5 / Q000378:metabolism; D004110:Diltiazem / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020441:Ginkgo biloba / Q000737:chemistry*; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008745:Methylation; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D015786:Cytochromes b5; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D004110:Diltiazem