Elsevier

Food and Chemical Toxicology

Volume 45, Issue 12, December 2007, Pages 2441-2445
Food and Chemical Toxicology

Herb–drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats

https://doi.org/10.1016/j.fct.2007.05.023Get rights and content

Abstract

Herbal medicines have received great attention as alternative medicines in recent years and are also referred to as a dietary supplement or health food. Ginkgo biloba extract (GBE) is one of the most popular herbal medicines. However, little is known about the metabolic interactions between GBE and clinically used drugs. This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window used for the treatment of asthma.

Commercial GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30% (GBE 10 mg/kg, P < 0.05) and 70% (GBE 100 mg/kg, P < 0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After oral administration of theophylline (10 mg/kg), the AUC0–24 h of theophylline was reduced by 40% following pretreatment with GBE (100 mg/kg, P < 0.01). These results demonstrate that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.

Introduction

The alkaloid theophylline is a potent bronchodilator with a narrow therapeutic index in serum concentration for the therapeutic range of 5–20 mg/L (Ohnishi et al., 2003). Almost 90% of theophylline is metabolized in the human liver by members of the cytochrome P450 (CYP) family, CYP1A2 and CYP2E1 (Ogilvie, 1978). The main pathways for theophylline metabolism in humans have been acknowledged to be N-1 or N-3 demethylation, which may be mediated by CYP1A2 and C-8 oxidation, which may be mediated by CYP1A2 and CYP3A4 (Grygiel et al., 1984, Campbell et al., 1987, Rogge et al., 1988, Gu et al., 1992, Sarkar et al., 1992). In contrast, in rats the theophylline is metabolized to 1,3-dimethyluric acid via CYP1A2 and CYP2E1 and to 1-methylxanthine via CYP1A2 which was further metabolized to 1-methyluric acid via xanthine oxidase (Teunissen et al., 1985). CYP1A2 is the major metabolizing enzyme for theophylline metabolism, so the drugs affecting the activity of CYP1A2 should change the theophylline clearance (Jonkman and Upton, 1984). Drugs, such as macrolide antibiotics, ciprofloxacin, allopurinol and cimetidine that interfere with hepatic metabolism, will reduce the clearance of theophylline (Barnes, 2003). Monitoring theophylline levels in plasma may be necessary, especially in elderly patients treated concomitantly with many drugs and in the long-term health care of asthmatic patients.

Ginkgo biloba L. is the oldest living tree on earth, dating back to the Paleozoic period, over 225 million years ago. The medicinal use of ginkgo leaf is first mentioned in Chinese medicine in the Ming dynasty in 1436 (Foster, 1996). A standardized extract of ginkgo leaf is one of the most clinically tested and frequently prescribed phytomedicines in Europe, and has been one of the 10 best-selling herbal dietary supplements in the US for about six years (Blumenthal et al., 1998, Blumenthal, 2001). The primary active components of GBE include 5–7% terpene lactones (ginkgolides and bilobalide) and 22–27% ginkgo flavonol glycosides (e.g., the flavones quercetin, kaempferol, and isorhamnetin) (Kressmann et al., 2002). G. biloba extract (GBE) is approved in Germany for the treatment of cerebral insufficiency (memory loss that occurs with conditions such as Alzheimer’s disease, vascular or multi-infarct dementia, and other conditions), tinnitus (ringing in the ears), vertigo, and intermittent claudication (poor circulation to the lower legs). In the US, ginkgo is used widely as a complementary therapy for Alzheimer’s disease and vascular dementia (Oken et al., 1998). Side effects of GBE are very rare and mainly include mild gastric upset, headache and allergic skin reactions (McKenna et al., 2001). Clinical cases have been reported in which GBE has been given concomitantly with aspirin, warfarin or trazodone and associated with spontaneous hyphema, intracerebral haemorrhage and acute depression, respectively (Fugh-Berman, 2000, Galluzzi et al., 2000).

GBE reduced the therapeutic potency of phenobarbital via enhancement of CYP2B expression (Kubota et al., 2004). Sugiyama et al. reported that pretreatment with GBE significantly attenuated the hypoglycemic action of tolbutamide in elderly rats, corresponding well to the enhanced catalytic activity of (S)-warfarin 7-hydroxylase, which belongs to the CYP2C9 subtype, a major isoform metabolizing tolbutamide (Sugiyama et al., 2004a). The feeding of GBE for 4 weeks significantly reduced the hypotensive effect of nicardipine which is metabolized by CYP3A2 in rats (Shinozuka et al., 2002). Rats were fed a GBE-containing diet or received GBE by intragastric gavage. The concentration of CYP and activity of various CYP enzymes (containing CYP1A1, CYP1A2, CYP2B, CYP2E1 CYP3A and CYP2C9) in the liver were increased in a dose- and time-dependent manner. Significant increases in the concentration and activities of CYP enzymes were detected on day 1 of feeding of a 0.5% GBE diet and after administration of 10 mg GBE/kg body weight for 5 days by intragastric gavage. The activity of CYP1A2 was markedly increased, with an increase by 80% at a dose of 10 mg/kg, and by 120% at a dose of 100 mg/kg (Umegaki et al., 2002). However, there is little information about the effects of GBE on the in vivo pharmacokinetics of CYP1A2 substrates such as theophylline in animals or humans. Therefore, we attempted to evaluate the pharmacokinetic interaction between GBE and theophylline in rats using commercially available standardized GBE in this study.

Section snippets

Chemicals and reagents

G. biloba extract (GBE) was purchased from Zhejiang Conba Pharmaceutical Co., Ltd. (Lanxi, Zhejiang, China). The GBE contained 26.1% flavonoids and 8.9% total terpenes, consisting of 2.3% ginkgolide A, 1.5% ginkgolide B, 1.1% ginkgolide C and 4.0% bilobalide. Theophylline and caffeine were supplied by the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). HPLC-grade methanol, diethyl ether and dichloromethane were from Concord Tech. Co. (Tianjin,

Results

The plasma concentration–time curves of theophylline after administration via the femoral vein at the dose of 10 mg/kg, with or without GBE pretreatment, are shown in Fig. 1. The pharmacokinetic parameters of theophylline indicated that pretreatment of rats with GBE at daily dosages of 10 mg/kg and 100 mg/kg for five consecutive days resulted in a 20.0% (P > 0.05) and a 37.8% (P < 0.01) reduction in the AUC0–24 h of theophylline, respectively. The elimination half-life of theophylline was

Discussion

CYP1A2 is expressed principally in the liver (Rendic and Di Carlo, 1997). CYP1A2 accounts for about 10–15% of the total CYP content of human liver and mainly metabolizes important drugs such as phenacetin, theophylline, caffeine, imipramine, propranolol, clozapine, tacrine (Brosen, 1995, Cupp and Tracy, 1998), and also activates some procarcinogens to carcinogens. CYP1A2 plays a role in human tobacco-related cancers (Smith et al., 1996).

Theophylline is predominantly metabolized by CYP1A2, and

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