In vitro and in silico evaluation of the interaction of yohimbine with drug transporters and cytochrome P450 isoenzymes.

Yohimbine is a food supplement that is also used to treat erectile dysfunction. It has recently been introduced as a probe drug to assess the activity of cytochrome P450 (CYP) 2D6. This in vitro study investigated possible substrate and inhibitor properties of yohimbine for drug transporters and inhibitor properties for CYPs to assess, whether yohimbine might be prone to drug-drug interactions. Inhibition of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptides (OATPs) and organic cation transporters (OCTs) was tested by using probe substrates and transporter-overexpressing cell lines. The potential substrate properties of yohimbine for P-gp and OCTs were tested in accumulation assays in different cell lines with and without overexpression of the respective transporter. Inhibition of CYPs was assessed by using luminogenic substrates. The interaction of yohimbine with OCTs was evaluated in silico using docking analyses. Yohimbine did not inhibit P-gp, BCRP, OATP 1B1, 1B3 and 2B1. It was described and characterised in vitro and in silico as a good substrate of OCT1-3 (K between 3.7 and 6.2 μM) and a weak inhibitor of OCT2 and OCT3 with IC values in the upper micromolar range. Yohimbine potently inhibited CYP2D6 with an IC of 0.31 μM, weakly inhibited CYP1A2, CYP2C19, and CYP3A4, and did not inhibit CYP2B6. In conclusion, we have verified that yohimbine inhibits CYP2D6 and demonstrated that it is a substrate of OCT1, OCT2, and OCT3, a weak inhibitor of OCT2 and OCT3, but does not inhibit P-gp, BCRP, OATP1B1, OTP1B3, OATP2B1, and OCT1.