Induction of Propranolol Metabolism by Ginkgo biloba Extract EGb 761 in Rats

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 Ndesisopropylpropranolol (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 (C max ) 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 α-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.

Effect of Ginkgo biloba on Blood Pressure and Incidence of Hypertension in Elderly Men and Women

“…Thus, it is possible that the effects of these medications washed out any potential effect of ginkgo biloba . Moreover, there is some indication that ginkgo biloba may interact with specific classes of antihypertensive medications to alter their pharmacological effects 17–19. For this reason, we are currently examining the interaction between type of antihypertensive medication and treatment group on BP in the GEM study.…”

Bilobalide in ginkgo biloba extract is a major substance inducing hepatic CYPs

“…The enzyme induction by bilobalide at the dose of 10.5 mg kg −1 was 13.8 times higher than in the untreated control (Table 3). As GBE is a natural product that gives a variety of products with different compositions, identification of a substance that induces hepatic CYPs is critical for standardizing GBE products and to avoid GBE-drug interactions, which are suggested by studies in animals (Kubota et al 2003(Kubota et al , 2004Sugiyama et al 2004a;Zhao et al 2006) and man (Yin et al 2004;Uchida et al 2006). Various studies have been performed to identify the active substance in GBE, but no clear data have been obtained so far.…”

Oxidative demethylenation and subsequent glucuronidation are the major metabolic pathways of berberine in rats

“…The effects of several human selective P450 inhibitors on the formation of the Phase I metabolites M1 and M2 in rat liver microsomes were investigated. The inhibitors used were: α‐naphthoflavone (for CYP1A),17 quinidine (for CYP2D1),18 orphenadrine (for CYP2B),19, 20 diethyldithiocarbamate (for CYP2E1),21 sulfaphenazole (for CYP2C6/11),22 and ketoconazole (for CYP3A1/2) 23. The concentrations used for BBR were 10, 50, and 200 µM and the concentrations of various inhibitors used were 2 and 10 µM for quinidine, 1 and 10 µM for α‐naphthoflavone, 10 and 50 µM for sulfaphenazole, 25 and 50 µM for orphenadrine, 12.5 and 25 µM for diethyldithiocarbamate, 1 and 10 µM for ketoconazole.…”