Trade Herbal Products and Induction of CYP2C19 and CYP2E1 in Cultured Human Hepatocytes

Abstract

The aim of this study was to evaluate in vitro the dose-dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S-mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP-modulating herb, showing a dose-dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log-linear dose-dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non-inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug-herb interactions with selected CYP2C19 substrates.

Valerian: No evidence for Clinically Relevant interactions

“…The authors conclude that both CYP 3A4 and P-gp interactions are unlikely to be clinically relevant, as the systemic concentrations are probably much lower; therefore, respective IC 50 values for P-gp cannot be reached in vivo. This conclusion is also applicable to their previous study [36] and to their study on CYP 2C19, which showed a weak induction by valerian root extracts [47].…”

The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review

“…[38][39][40][41] Phenobarbital is a typical enzyme inducer of CYP2C9 and CYP3A4, which presents a weak induction effect (20-50% decrease in substrates' AUC) .38,42-44 Several studies have shown that repeated doses of efavirenz and St John's wort had a significant induction effect on both CYP2C19 and CYP3A4 in vivo. [45][46][47][48][49][50][51][52][53] Thus, in our study these two drugs may enhance voriconazole metabolism through the induction of the above enzymes. In previous studies, ritonavir has been found to be a potent inhibitor of CYP3A4.…”

Herbal drugs and drug interactions

“…They also studied the induction capacity of some herbal drugs on CYP1A2, CYP2D6, CYP2C19, CYP2E1 and CYP3A4 metabolic activities in cultured human hepatocytes and reported that Ginkgo biloba may exert opposite and biphasic effects on CYP1A2, CYP2C19, CYP2E1 and CYP2D6 metabolic activities. Induction of CYP1A2, CYP2C19, CYP2E1 and inhibition of CYP2D6 were found at low concentrations; the opposite was observed at high concentrations (64,102). They reported that inducing effect of Ginkgo biloba was close to that of SJW.…”

“…Hellum et al (2009) reported that among the herbal drugs they studied, SJW was the most potent CYP-modulating herb, showing a dose-dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher (64).…”