Effect of valerian root extracts (Valeriana officinalis) on acetaminophen glucuronidation: in vitro and in vivo studies

Herbal products have been shown to cause serious interactions when combined with conventional medications. A majority of these interactions are pharmacokinetic in nature and involve alteration in the activity of drug metabolizing enzymes. Valerian is a popular herbal product often used to treat insomnia and anxiety. Valerian extracts contain essential oils with sesquiterpenes such as valerenic acid and its derivatives. However, the drug interaction potential of valerian preparations is largely unknown. In human liver microsomes, valerenic acid forms a glucuronide conjugate suggesting that valerian extracts could interact with drugs that undergo glucuronidation. As glucuronidation is catalyzed by UDP- glucuronosyltransferase enzymes (UGT), the goal of this dissertation was to investigate the effect of valerian extracts on UGT activity. Acetaminophen was used as a probe substrate to measure UGT activity in these studies. A bioassay-guided fractionation approach was adopted to identify the major compounds in valerian extracts that are responsible for inhibition of UGT activity. The alcoholic extract of valerian was fractionated by liquid-liquid extractions followed by chromatographic methods. The organic extracts showed significant inhibitory activity compared to the aqueous extracts. Using various chromatographic and spectroscopic techniques, the major compounds present in the active fraction were identified as valerenic acid, acetoxyvalerenic acid and valerenal. The clinical implications of the inhibition of UGT enzymes by valerian extracts were investigated in a study in healthy human volunteers. Valerian administration resulted in an increased acetaminophen maximum plasma concentration (Cmax) and a decrease in time to reach the maximum plasma concentration (tmax), but did not affect the area under the plasma concentration-time curve (AUC) or half life. As these results were unexpected, human hepatocyte cultures were used to determine if enzyme induction potential of some components may offset the inhibition of UGT enzymes. We hypothesized that the inhibition observed in the microsomal study could be masked by an increase in enzyme activity due to induction of enzymes by chronic exposure to the extracts. In human hepatocyte cultures, valerian extracts inhibited UGT activity on acute exposure while chronic exposure increased UGT activity and mRNA levels. Our study indicates that there is no clinically significant interaction between acetaminophen and valereian. In vitro studies in human hepatocytes may better predict in vivo herb-drug interactions than studies in microsomes