Interaction of Ginkgo biloba with efavirenz

Abstract

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with a long half-life (approximately 45 h) allowing once-daily oral administration. As with the other NNRTI nevirapine, EFV is not only metabolized by cytochrome P450, family 3, subfamily A (CYP3A) isoenzymes, but also by CYP2B isoenzymes. EFV is highly bound to plasma proteins (99.5–99.7%) and is able to inhibit CYP3A4 and induce CYP2B6, CYP2C19 and CYP3A4 [1]. The recommended dosage of EFV is 600 mg every 24 h [2]. The therapeutic EFV plasma concentration range is 1.0–4.0 mg/l. Because of its metabolic route, not only negative drug–drug interactions, but also drug–herb interactions can occur. Here, we report virological failure in a 47-year-old HIV-infected patient who received antiretroviral therapy for 10 years. He had always been very drug-compliant, never missing a single dose. He was using EFV for 2 years in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). At the end of 2007, a virological failure developed, and a K103N and M184V mutation in the reverse transcriptase gene was demonstrated. After directed questioning, the patient appeared to be using Ginkgo biloba for some months. No other comedication was used or discontinued in this timeframe. To explain the virological failure, plasma EFV concentration measurements were conducted on several plasma samples dating back 2 years. Concentrations of EFV decreased over time, coinciding with an increase in viral load (Table 1). From March 2008, the patient was successfully switched to alternative antiretroviral therapy.Table 1: HIV-1 RNA copies measured in plasma and efavirenz plasma concentrations.Ginkgo biloba is one of the most widely used herbal drugs in the world. It is commonly used because of its assumed beneficial effects on concentration, memory, dementia and depressive disorders. Ginkgo biloba extract (GBE) is made of Ginkgo leaves and is usually standardized to contain 24% flavonoids (quercetin, kaempferol and isorhamnetin), 6% terpenoids (ginkgolides A, B, C, J, M and bilobalide) and not more than 5 ppm organic acids (ginkolic acids and alkylphenols) [3]. Examining the properties of the constituents of GBE, the effects on cytochrome P450 metabolic routes can be anticipated. Research has shown that flavonoids can inhibit P-glycoprotein (P-gp) and CYP3A4 [3,4]. Terpenoids can induce P-gp, pregnane X receptor (PXR), multidrug-resistance 1 (MDR-1) and CYP3A4 [5], and organic acids can inhibit CYP2C9, CYP2C19, CYP2D6 and CYP3A4 [6]. Gingko biloba has been confirmed to interact with a number of drugs that are metabolized through cytochrome P450 isoenzymes (e.g. trazodone, warfarin, aspirin, ibuprofen, digoxin and omeprazole) [6]. In this case, we believe that the terpenoids have caused the negative pharmacokinetic interaction with EFV either by induction of CYP3A4 or P-gp. Not only strong inducers of CYP3A4, such as rifampicine, have often been described to lower NNRTI plasma levels leading to virological failure, but also induction of P-gp might have similar effects. P-gp is an ATP-dependant efflux transporter, which is known to transport various types of drugs out of the brain, out of the gonads, into the bile, into the urine and into the gut lumen. As EFV is metabolized by CYP3A4, it is likely that EFV also interacts with P-gp as has been observed for various cationic and lipophilic drugs. Indeed, Fellay et al. [7] have shown that single-nucleotide polymorphisms of P-gp have significant impacts on human plasma EFV levels. Therefore, the decrease of EFV plasma levels in this particular clinical case may also have been caused by induction of P-gp. Although the exact underlying mechanism remains unresolved, terpenoids in GBE may lower EFV plasma levels by the induction of CYP3A4 and P-gp. We conclude that an intake of GBE can decrease human plasma EFV levels, may result in virological failure and should be discouraged.