Induction of propranolol metabolism by Ginkgo biloba extract EGb 761 in rats.

Full Abstract

Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form N-desisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by alpha-naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.

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Author information

Author/s: Zhao, Li-Zi (LZ); Huang, Ming (M); Chen, Jie (J); Ee, Pui Lai Rachel (PL); Chan, Eli (E); Duan, Wei (W); Guan, Yong-Yuna (YY); Hong, Yun-Han (YH); Chen, Xiao (X); Zhou, Shufeng (S);

Affiliation: Institute of Clinical Pharmacology, Sun Yat-sen University, Guangzhou, China.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Current drug metabolism (Curr Drug Metab), published in Netherlands. (Language: eng)

Reference: 2006-Aug; vol 7 (issue 6) : pp 577-87

Dates: Created 2006/08/21; Completed 2006/09/14; Revised 2006/11/15;

PMID: 16918313, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Atrial Natriuretic Factor - pharmacology
Cytochrome P-450 Enzyme System - metabolism
Drug Interactions
Ginkgo biloba
Liver - metabolism

Male
Plant Extracts - pharmacology
Propranolol - analogs & derivatives; metabolism; pharmacokinetics
Quinidine - pharmacology
Rats
Rats, Sprague-Dawley

Associated Chemicals: Ginkgo biloba extract 761 (0) ; Plant Extracts (0) ; N-desisopropylpropranolol (20862-11-7) ; Propranolol (525-66-6) ; Quinidine (56-54-2) ; Atrial Natriuretic Factor (85637-73-6) ; Cytochrome P-450 Enzyme System (9035-51-2)

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