Determination of yohimbine and its two hydroxylated metabolites in humans by high-performance liquid chromatography and mass spectral analysis

doi:10.1016/0378-4347(92)80041-N

Journal of Chromatography B: Biomedical Sciences and Applications

Volume 574, Issue 2, 14 February 1992, Pages 283-292

https://doi.org/10.1016/0378-4347(92)80041-N Get rights and content

Abstract

The existence of at least two metabolites of yohimbine (YO) in humans is demonstrated. Combined high-performance liquid chromatographic (HPLC), NMR and mass spectral analyses permitted them to be identified as hydroxylated metabolites at the C-10 and C-11 positions. A normal-phase HPLC method allowing the simultaneous determination of YO and its main metabolite, 11-hydroxyyohimbine (11-OHYO), in biological samples is described. This assay was performed using a LiChrosorb Si 60 column and a mobile phase consisting of 0.02 M sodium acetate (pH 5)—methanol (5:95, v/v) at a flow-rate of 1 ml/min. Detection was achieved by a fluorimetric method (excitation at 280 nm and emission at 320 nm). The extraction yields of YO, 10-OHYO and 11-OHYO from plasma were 91.8, 45.3 and 17.8%, respectively, and their respective within-day reproducibilities were 3.8, 1.4 and 5.9%. The between-day reproducibility for YO at the concentrations of 1 and 10 ng/ml were 8.9 and 6.4%, respectively. The accuracy of the method for YO at concentrations of 1 and 10 ng/ml were 5.1 and 2.3%, respectively. The limits of determination of YO, 10-OHYO and 11-OHYO were 0.1, 0.5 and 1 ng/ml, respectively. The method was used in bioavailability study of YO following oral and intravenous administration in humans.

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Citation Excerpt :
Even though the elimination half life is only 0.25 to 2.5 h, the active metabolite 11-Hydroxyyohimbin, which acts in a very similar manner to that of yohimbine itself, has a considerably longer half life of approximately 6 h (professional information Yocon-Glenwood, Glenwood GmbH). The effect of this metabolite explains, according to Le Verge et al. (1992), the long lasting therapeutic effects of yohimbine that clearly exceed its actual half life. As can be seen from Fig. 1, the gambling task started approximately 85 min after yohimbine administration which, due to the preceding fear conditioning and extinction experiment, is slightly after the ideal time window of maximum yohimbine plasma concentration.
External and internal performance feedback triggers not only neural but also cardiac modulations, suggesting communication between brain and heart during feedback processing. Using Cardio-Electroencephalographic Covariance Tracing (CECT), it has accordingly been shown that feedback-evoked centromedial single-trial EEG at the P300 latency intraindividually predicts subsequent changes in heart period – the so called N300H phenomenon. While previous findings suggest that the N300H depends on serotonin, its relationship to central dopamine and noradrenaline is currently unknown. Here, we tested (1) the psychometric properties of this CECT-based component and (2) its putative catecholaminergic mechanisms. N = 54 healthy male participants received either a α2-adrenoceptor antagonist (yohimbine, 10 mg; n = 18), D₂-dopamine-receptor antagonist (sulpiride, 200 mg; n = 18), or a placebo (n = 18). Afterwards, they performed a gambling task with feedback after each trial, while EEG and ECG were recorded. Feedback successfully evoked a significant N300H both across all 54 participants and within each substance group. Importantly, we show that N300H can be reliably measured in a priori defined time windows with as few as 240 feedback trials and is relatively unaffected when removing extreme single-trial values. However, we could not find any significant substance effects on N300H magnitude as well as on univariate feedback-related measures (FRN, P300, heart period). Altogether, the N300H component proves as a robust and reliable marker of cortico-cardiac coupling evoked by feedback. Furthermore, these findings suggest a subordinate role of catecholamines (i.e., noradrenaline and dopamine) and sympathetic pathways in feedback-evoked brain-heart communication as measured with N300H.
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The metabolism and pharmacology of naturally-occurring alkaloids are reviewed, with emphasis on work of the last ten years during which there have been many important advances. It is recognized that the final effects of alkaloids on animals may result from activity of their metabolic products rather than of the original substance. Therefore one section discusses how alkaloids are metabolized, first in terms of the general processes and then with many examples of the metabolism of particular types of alkaloid structures. The second section on pharmacology deals with detailed biochemistry of alkaloid action at the level of molecule-to-molecule, rather than describing behavioral or gross physiological effects. Modern molecular biological methods have revealed the intimate structures of neural receptors and other cellular molecules with which the alkaloids interact. In this section of the review the material is organized according to the processes being affected rather than according to types of alkaloid. Thus there are subsections for the various neural receptors, structural components of cells, enzymes, etc.
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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.
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To assess whether activation of platelets by catecholamines contributes to the increase in platelet aggregation associated with either the assumption of upright posture or exercise, we studied the effect of oral yohimbine on these phenomena. Whole blood platelet aggregation and plasma catecholamine levels were measured before and after standing and at peak exercise in untreated normal subjects and after oral yohimbine. Neurochemical indexes indicated systemic α₂-receptor blockade by yohimbine. Yohimbine reduced the orthostatic increase in platelet aggregation response by 63 ± 11%, but exercise-induced increase in aggregation was unaffected. Thus, α₂-adrenergic blockade attenuates the orthostatic increase in platelet aggregation. Agents designed to inhibit the morning surge in catecholamine levels or block platelet α₂ adrenoceptors may reduce the risk of thrombotic vascular events in atherosclerosis.

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Determination of yohimbine and its two hydroxylated metabolites in humans by high-performance liquid chromatography and mass spectral analysis

Abstract

Am. Heart J.

Brain Res.

J. Urol.

J. Chromatogr.

J. Chromatogr.

J. Chromatogr.

Pharmacol. Rev.

Neurology

Clin. Pharmacol. Ther.

Br. J. Clin. Pharmacol.