YOHIMBINE ELIMINATION IN NORMAL VOLUNTEERS IS CHARACTERIZED BY BOTH ONE-COMPARTMENT AND 2-COMPARTMENT BEHAVIOR

We sought to determine the safety, pharmacodynamic response, and singl e- and multiple-dose pharmacokinetic profile of yohimbine hydrochlorid e. 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 twi ce daily (b.i.d.), with determination of plasma catecholamine levels a nd mood/anxiety-inventory scores. The pharmacokinetic profile of yohim bine was determined after the first and last dose. Yohimbine exhibited one-compartment elimination in most subjects, with dose-dependent inc reases in maximal concentration (C-max) and area under the curve (AUC) but no evidence of drug accumulation. At least two subjects in each c ohort exhibited two-compartment elimination of yohimbine, with nonsign ificant increases in day 7 AUC, C-max, and terminal elimination half-l ife (t(1/2 beta)). Plasma catecholamine levels increased significantly in relation to both average yohimbine AUC and C-max but there were no significant effects on heart rate, blood pressure, or anxiety/mood-in ventory scores. The single- and multipledose pharmacokinetic profile o f yohimbine exhibits a substantial degree of interpatient and intrapat ient variability, possibly resulting from variability in first-pass an d hepatic metabolism. There is a significant correlation between plasm a norepinephrine levels and yohimbine AUC or C-max. Further multiple-d ose studies are warranted definitively to address the relation between yohimbine AUC or C-max and pharmacologic effect.