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

• Published in: Biological & Pharmaceutical Bulletin 2003, Vol.26(9), pp.1315-1320
• Main Authors: Ohnishi, Noriaki, Kusuhara, Mayako, Yoshioka, Mutsunobu, Kuroda, Kazuo, Soga, Akihiro, Nishikawa, Fumi, Koishi, Tomokazu, Nakagawa, Masato, Hori, Satoshi, Matsumoto, Tsuyoshi, Yamashita, Masayuki, Ohta, Shunsaku, Takara, Koji, Yokoyama, Teruyoshi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analytical, structural and metabolic biochemistry; Animals; Area Under Curve; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Biological and medical sciences; Calcium Channel Blockers - administration & dosage; Calcium Channel Blockers - pharmacokinetics; Cytochrome P-450 CYP3A; Cytochromes b5 - metabolism; diltiazem; Diltiazem - administration & dosage; Diltiazem - pharmacokinetics; Drug Interactions; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Ginkgo biloba - chemistry; Ginkgo biloba leaf; Half-Life; In Vitro Techniques; Injections, Intravenous; Intestine, Small - drug effects; Intestine, Small - enzymology; Intestine, Small - metabolism; Male; Medical sciences; metabolism; Methylation; Microsomes - drug effects; Microsomes - enzymology; Microsomes - metabolism; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Oxidoreductases, N-Demethylating - antagonists & inhibitors; P450; pharmacokinetic interaction; Pharmacology. Drug treatments; Plant Extracts - pharmacology; rat; Rats; Rats, Wistar
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.26.1315

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 IC50 of about 50 and 182 μg/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.