Compatibility risks between drugs and herbal medicines or botanical supplements

Abstract

Herbal supplements along with prescribed medicines raise concerns of therapeutic activity due to possible drug–herbal interactions. MDR gene products: P-gp, MRP and BCRP and metabolizing enzyme (cytochrome P450) together constitute a highly effective barrier for many orally absorbed drugs. Therapeutic agents and active herbal constituents are substrates, inhibitors and inducers of both P-gp and CYP3A4. Inhibition of P-gp by pure herbal constituents such as hypericin, kaempferol and quercetin or extract of St. John's wort resulted in higher absorption of ritonavir and erythromycin in vitro. Similarly, inhibition of CYP by hypericin, kaempferol and quercetin also caused a remarkable reduction in cortisol metabolism in vitro. Conversely, an enhanced expression of both CYP3A4 and MDR-1 mRNA in Caco-2 cells was observed after chronic exposure of hyperforin, kaempferol, quercetin and hypericin, kaempferol, quercetin, silibinin respectively. Chronic exposure (96h) of African herbal (Sutherlandia frutescens) extract (300μg/mL) resulted in elevation of both P-gp and CYP3A4 expressions in LS180V cells. Cellular accumulation of [3H]Digoxin, a model P-gp substrate was significantly reduced indicating higher efflux. These in vitro results were further confirmed in rats. Administration of Sutherlandia-extract for 4 days significantly affected pharmacokinetics of nevirapine – a CYP3A4 (CYP3A2) substrate. Plasma concentration of nevirapine was diminished by 51% (Cmax) and 45% (AUC0-inf) compared to controls. Similar pharmacokinetics of fexofenadine, a P-gp substrate was also observed. Plasma concentration of fexofenadine was declined by 49.7% (Cmax) and 34.5% (AUC0-inf) compared to controls. Hepatic CYP3A4 and P-gp mRNA levels were enhanced by 3-fold and 1.75-fold respectively. Intestinal CYP3A4 (2-fold) and P-gp expressions (3-fold) was also elevated. Such reduction of steady state plasma concentrations of nevirapine and fexofenadine after concomitant administration of Sutherlandia in rats suggests medicinal agents that are substrates for P-gp and/or CYP are likely to be potential candidates for drug–herbal interactions.