Studies on Interactions between Functional Foods or Dietary Supplements and Medicines. III. Effects of Ginkgo biloba Leaf Extract on the Pharmacokinetics of Nifedipine in Rats

Abstract

Standardized Ginkgo biloba leaf extract (GBE) is a widely used dietary supplement for the treatment or prevention of Alzheimer's disease, failing memory, age-related dementias, etc. in Japan as well as the United State, and now a phytomedicine in many countries in Europe.1) GBE consists of many flavonoid glycosides and various unique diterpenes such as ginkgolides, which are potent inhibitors of platelet activating factor.1) It is highly likely that GBE is used in combination with various medicines by many patients.Previously, we reported that the simultaneous addition of GBE to the rat small intestine and liver microsomes inhibited the formation of N-demethyl diltiazem (MA), an active metabolite of diltiazem (DTZ) produced by a well-known drug metabolizing enzyme P450 (CYP) 3A, in a concentration-dependent manner.2) 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. Furthermore, it was found the concomitant use of GBE in rats significantly increased the bioavailability after oral administration of DTZ, a typical substrate of CYP3A, as well as a highly extracted drug, while the elimination after intravenous administration of DTZ was slightly delayed by simultaneous oral treatment with GBE.2) These findings suggest that there is a possibility of potential pharmacokinetic interactions between GBE and other drugs that are both substrates for CYP3A and extensively extracted drugs.3,4) However, there are still many unclear points regarding the inhibitory mechanism of action because DTZ is a substrate of not only CYP3A, but also esterase in rats and humans, 5) and of the multidrug transporter P-glycoprotein (P-gp) which is expressed in normal tissues with excretory function, playing an important role in drug pharmacokinetics. [6][7][8] Therefore, in this study, we examined the effects of simultaneous oral treatment with GBE on the pharmacokinetics of nifedipine (NFP), which is a representative substrate of CYP3A, but not P-gp, [6][7][8] and is at first metabolized only to dehydronifedipine (NFPO) in the intestine and liver in both rats and humans, 9-13) after intravenous and oral administration of NFP to rats. MATERIALS AND METHODSChemicals GBE (Ginkgolon-24; Lot No. 830301034) powders were kindly provided by Tokiwa Phytochemical Co., Ltd. (Chiba, Japan). GBE was produced using a standard method by extraction from milled leaves with ethanol. The final quality of this extract was assured by maintaining the prescribed range of index components (over 24% flavonoid glycosides and 6% terpene lactones and less than 1 ppm ginkgolic acids). NFP, nicardipine (an internal standard for HPLC analysis) and polyethylene glycol (PEG) 400 were purchased from Wako Pure Chemical Ind., Ltd. (Osaka, Japan). All other chemicals were reagent-or HPLC-grade commercial products.Animals Nine-week-old male Wistar rats (Japan SLC, Inc., Hama...

Evaluation of metabolism-mediated herb-drug interactions

“…This study demonstrated that pretreatment of GBE increased clearance of theophylline in rats by increasing CYP1A2 metabolic activity. Yoshioka et al (2004a) investigated the effects of GBE in rats on the pharmacokinetics of nifedipine (a calcium channel blocker) which is a typical probe of CYP3A, but not a substrate of the P-gp. These results suggest that the concomitant oral use of GBE and nifedipine in rats appeared to reduce the first-pass metabolism of the drug by inhibiting CYP3A, but not P-gp.…”

Effect of Ginkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers

“…In fact, available data for GBE effects on cytochrome P450 activity in vitro and in vivo from animal and human studies is inconsistent. In vitro studies in rat liver microsomes showed inhibitory effects of GBE on some CYPs [10–12], whereas both inhibition [13, 14] and induction [15–17] was reported for in vivo studies. In vitro experiments carried out in human liver microsomes suggested that GBE weakly inhibits human CYP enzymes, e.g., CYP1A2 and CYP3A [18].…”

Simultaneous Determination of 6,7-Dimethylesculetin and Geniposide in Rat Plasma and its Application to Pharmacokinetic Studies of Yin Chen Hao Tang Preparation

“…Due to the complexity of TCM in composition constituents [3], which usually interferes with the determination of target compounds, developing an efficient and accurate determination method is always at the cost of running time in chromatographic analysis or depends on optimal sample prepared method. To date, various analytical techniques have been developed to determine constituents in TCM; HPLC coupled with UV detection is by far the most commonly adopted method due to its efficiency and accuracy [4][5][6][7].…”