Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects

Abstract

Objective: Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre-and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.Methods: This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively.Results: Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC 0-∞ and C max by 34% ( p = 0.03) and 31% ( p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.Conclusions: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4.Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.

Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1

“…A study investigated the influence of Ginkgo biloba extract on the pharmacokinetics of fexofenadine [31]. After an intake of Ginkgo biloba extract (120 mg bid) for two weeks a non significant reduction by 20 % in fexofenadine AUC was observed.…”

Effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers

“…Unlike competitive enzyme inhibition, enzyme induction by G. biloba is a slow regulatory process because new protein must be synthesized. A 14-day pretreatment was chosen on the basis of previous in vivo studies [20][21][22] and to prevent unnecessarily long exposure of healthy volunteers to G. biloba.…”

Effect of Ginkgo Biloba on the Pharmacokinetics of Raltegravir in Healthy Volunteers

“…Although ginkgo biloba extract has potential beneficial effects, self-medication with ginkgo biloba may lead to undesirable drug interactions with regular medication. For example, a study in healthy subjects showed that plasma concentrations of midazolam (a CYP3A probe) were significantly reduced after ginkgo biloba intake (22). If this were also true with antiretroviral agents, it could place individual patients at risk for virological failure.…”