PHARMACOKINETICS OF VENLAFAXINE AND O-DESMETHYLVENLAFAXINE IN LABORATORY-ANIMALS

1. The pharmacokinetics of venlafaxine have been evaluated in mouse, r at, dog and rhesus monkey after i.v. and/or i.g. doses of venlafaxine from 2 to 120 mg/kg either as single or repeated doses. 2. In rat, dog and monkey, venlafaxine is a high clearance compound with a large vol ume of distribution after i.v. administration. 3. Absolute bioavailabi lity was low in rat and rhesus monkey (12.6 and 6.5%, respectively) an d moderate in dog (59.8%). Other species differences were seen, includ ing an elimination half-life of venlafaxine that was longer in dog and rhesus monkey (2-4 h) than in rodent (around 1 h). 4. In mouse, rat a nd dog, exposure to venlafaxine increased more than proportionally wit h dose, suggesting saturation of elimination. Exposure of venlafaxine decreased with repeated dosing in mouse and rat, but was unchanged in dog. 5. Exposure of animals to the bioactive metabolite, O-desmethylve nlafaxine (ODV), was less than that of venlafaxine itself. ODV was not detected in dog and not measurable in rhesus monkey receiving venlafa xine.