Biopharmaceutics and metabolism of yohimbine in humans

Abstract

The biopharmaceutics of yohimbine (YO) and the pharmacokinetics of 10-hydroxy-yohimbine (10-OH-YO) and 11-hydroxy-yohimbine (11-OH-YO) were investigated in healthy subjects following i.v. (5 mg) and oral (8 mg) dosing. One subject was found as a slow hydroxylator of YO. The mean (±S.D.) oral absolute bioavailability of YO was 22.3±21.5%. Total plasma clearance (CL) and renal clearance (CL_r) of YO following i.v. dosing were 0.728±0.256 ml/min and 0.001±0.002 ml/min, respectively. Based on the steady-state volume of distribution (V_ss), YO had a relatively low distribution (V_ss=32.2±12.1 l). The overall renal excretion of YO, 10-OH-YO and 11-OH-YO, expressed as percent of the dose of YO administered, were not different following i.v. and oral dosing, and were around 0.1, 0.2 and 14%, respectively. Following i.v. dosing of YO, the mean apparent terminal half-life of 11-OH-YO (347±63 min) was almost four times higher than that of YO (91.0±33.6 min) suggesting an elimination rate-limited kinetics for 11-OH-YO.

Introduction

Yohimbine (YO) is a selective α-2-adrenergic antagonist used as a probe for differentiating α-receptor subtypes (Goldberg and Robertson, 1983). YO can also be used as a probe to evaluate the sympathetic reactivity in essential hypertension (Goldstein et al., 1991) and vulnerability to affective and anxiety disorders (Mendlewicz et al., 1989). YO is also used as a pharmacologic probe of the central noradrenergic system. Indeed, it has been shown, following YO administration, that the increase in cerebrospinal fluid levels of norepinephrine in normal older persons and patients with Alzheimer’s disease was higher than those measured in young healthy subjects (Peskind et al., 1995).

Yohimbine is used clinically for the management of impotence (Morales et al., 1987), for the treatment of orthostatic hypotension secondary to autonomic failure (Onrot et al., 1987) and tricyclic antidepressant therapy (Lacomblez et al., 1989), dry mouth (Chatelut et al., 1989, Bagheri et al., 1992, Bagheri et al., 1994) and to induce lipid mobilization in obese subjects (Berlan et al., 1991).

The pharmacokinetics of YO has been investigated in young healthy subjects (Owen et al., 1987, Guthrie et al., 1990, Hedner et al., 1992, Sturgill et al., 1997), in normal older persons and patients with Alzheimer’s disease (Le Corre et al., 1997) and in middle-aged patients treated with antidepressant drugs (Bagheri et al., 1994) showing that YO has a high and variable plasma clearance. The oral bioavailability of YO was shown to be low and variable (Guthrie et al., 1990). In addition, we have shown that YO was metabolized in at least two metabolites, namely 10-hydroxy-yohimbine and 11-hydroxy-yohimbine (11-OH-YO) (Le Verge et al., 1992), and that both YO and 11-OH-YO are distributed in cerebrospinal fluid (Le Corre et al., 1997). The 11-hydroxy metabolite which is the only metabolite detected in plasma was shown to have α-2-adrenergic antagonist properties (Berlan et al., 1993).

In order to get further insight in the biopharmaceutics and metabolism of YO, we investigated the disposition of yohimbine and of its hydroxylated metabolites following intravenous and oral dosing in healthy subjects.