The Potential of Sutherlandia frutescens for Herb-Drug Interaction

Sutherlandia frutescens (ST) is a popular medicinal herb widely consumed in Africa by people living with HIV/AIDS. Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction. This study investigated the inhibitory effects of the crude extracts of ST on the major cytochrome P450 isozymes employing pooled human liver microsomes. Its effect on the metabolic clearance of midazolam using cryopreserved hepatocytes was also monitored. The potential of ST to inhibit human ATP-binding cassette (ABC) transporters (P-gp and BCRP) and the human organic anion transporting polypeptide (OATP1B1 and OATP1B3) activity was assessed using cell lines overexpressing the transporter proteins. ST showed inhibitory potency for CYP1A2 (IC50 = 41.0 μg/mL), CYP2A6 (IC50 = 160 μg/mL), CYP2B6 (IC50 = 20.0 μg/mL), CYP2C8 (IC50 = 22.4 μg/mL), CYP2C9 (IC50 = 23.0 μg/mL), CYP2C19 (IC50 = 35.9 μg/mL) and CYP3A4/5 (IC50, = 17.5 μg/mL [with midazolam1'-hydroxylation]; IC50 = 28.3 μg/mL [with testosterone 6β-hydroxylation]). Time-dependent (irreversible) inhibition by ST was observed for CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) under the conditions of this study. ST also delays the production of midazolam metabolites in the hepatocytes, decreasing its clearance by 40%. Further, ST inhibited P-gp (IC50 = 324.8 μg/mL); OATP1B1 (IC50 = 10.4 μg/mL, and of OATP1B3 (IC50 = 6.6 μg/mL). The result indicates the potential for HDI between ST and the substrates of the affected enzymes, if sufficient in vivo concentration of ST is attained.