Metabolic disposition of¹⁴C-venlafaxine in mouse, rat, dog, rhesus monkey and man

Abstract

1. The metabolic disposition of venlafaxine has been studied in mouse, rat, dog, rhesus monkey and man after oral doses (22, 22, 2, and 10 mg/kg, and 50 mg, respectively) of 14C-venlafaxine as the hydrochloride. 2. In all species, over 85% of the administered radioactivity was recovered in the urine within 72 h, indicating extensive absorption from the GI tract and renal excretion. 3. Venlafaxine was extensively metabolized, with only 13.0, 1.8, 7.9, 0.3 and 4.7% dose appearing as parent compound in urine of mouse, rat, dog, monkey and man, respectively. The metabolite profile varied significantly among species, but primary metabolic reactions were demethylations and the conjugation of phase I metabolites. Hydroxylation of the cyclohexyl ring also occurred in mouse, rat and monkey, and a cyclic product was formed in rat and monkey. Glucuronidation was the primary conjugation reaction, although sulphate conjugates were also detected in mouse urine. 4. While no metabolite constituted more than 20% dose in any species except man, the major urinary metabolites were: mouse, N,O-didesmethyl-venlafaxine glucuronide; rat, cis-1,4-dihydroxy-venlafaxine; dog, O-desmethyl-venlafaxine glucuronide; monkey, N,N,O-tridesmethyl-venlafaxine; and man, O-desmethyl-venlafaxine.

Regulation of Corticotropin-Releasing Factor Neuronal Systems and Hypothalamic-Pituitary-Adrenal Axis Activity by Stress and Chronic Antidepressant Treatment

“…(Troy et al, 1995). The metabolite, O-desmethylvenlafaxine, was undetectable in rat serum, in agreement with a previous report (Howell et al, 1993). Tranylcypromine, 1.5 to 2.0 mg/kg/day: previous investigators' findings in rats given tranylcypromine via minipump, such as 85 to 95% monoamine oxidase A and B inhibition after 1.28 mg/kg/day (Hampson et al, 1988).…”

An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

“…Desvenlafaxine was recently approved for the treatment of major depressive disorder (MDD) (project listing at http://www.wyeth.com/research/projects, Wyeth Pharmaceuticals, 2007;Wyeth Pharmaceuticals, 2008). The biotransformation of venlafaxine to desvenlafaxine is dependent primarily on the CYP2D6 enzyme system (Shams et al, 2006); more than 55% of an oral dose is recovered as desvenlafaxine and its glucuronide conjugate in the urine within 48 h after administration (Howell et al, 1993;Otton et al, 1996). However, desvenlafaxine is mainly eliminated unchanged by renal excretion and to a lesser extent is metabolized by phase II enzymes to form a glucuronide conjugate (Parker et al, 2005;Wyeth Pharmaceuticals, 2008).…”

Which Metabolites Circulate?

“…The systemic exposure of this metabolite was four-to sixfold higher than that of parent in CYP2D6 extensive metabolizers (EM) (Patat et al, 1998;Hynninen et al, 2008). Furthermore, although a significant portion of the dose (26%) was excreted in urine as the glucuronide conjugate of desvenlafaxine, 29% of the dose was excreted as the aglycone (Howell et al, 1993). Also, after oral administration of desvenlafaxine, renal clearance constitutes a major clearance mechanism for the parent (DeMaio et al, 2011).…”

“…O-Dealkylation of venlafaxine resulted in the formation of desvenlafaxine (Fig. 5) (Howell et al, 1993). The systemic exposure of this metabolite was four-to sixfold higher than that of parent in CYP2D6 extensive metabolizers (EM) (Patat et al, 1998;Hynninen et al, 2008).…”