Yohimbine elimination in normal volunteers is characterized by both one- and two-compartment behavior

We sought to determine the safety, pharmacodynamic response, and single- and multiple-dose pharmacokinetic profile of yohimbine hydrochloride. Thirty-two healthy volunteers received 6 days of yohimbine, 5.4 mg 3 times daily (t.i.d.), 10.8 mg t.i.d., 16.2 mg t.i.d., or 21.6 mg twice daily (b.i.d.), with determination of plasma catecholamine levels and mood/anxiety-inventory scores. The pharmacokinetic profile of yohimbine was determined after the first and last dose. Yohimbine exhibited one-compartment elimination in most subjects, with dose-dependent increases in maximal concentration (Cmax) and area under the curve (AUC) but no evidence of drug accumulation. At least two subjects in each cohort exhibited two-compartment elimination of yohimbine, with nonsignificant increases in day 7 AUC, Cmax, and terminal elimination half-life (t1/2beta). Plasma catecholamine levels increased significantly in relation to both average yohimbine AUC and Cmax, but there were no significant effects on heart rate, blood pressure, or anxiety/mood-inventory scores. The single- and multiple-dose pharmacokinetic profile of yohimbine exhibits a substantial degree of interpatient and intrapatient variability, possibly resulting from variability in first-pass and hepatic metabolism. There is a significant correlation between plasma norepinephrine levels and yohimbine AUC or Cmax. Further multiple-dose studies are warranted definitively to address the relation between yohimbine AUC or Cmax and pharmacologic effect.