Journal of Bioequivalence & Bioavailability

Abstract

Metabolism Studies of Desvenlafaxine

William DeMaio, Cecelia P. Kane, Alice I. Nichols and Ronald Jordan

Background: This series of experiments was conducted to describe the metabolic profile of the serotonin norepinephrine reuptake inhibitor desvenlafaxine (administered as desvenlafaxine succinate) using animal and human models. Methods: In vivo and in vitro experiments were conducted with humans and preclinical species (CD-1 mice, Sprague Dawley rats, and beagle dogs). Single oral doses of [14C]-desvenlafaxine were administered to each preclinical species for analyses of desvenlafaxine concentration in plasma, urine, and feces. Rats also were subjected to whole body autoradiography and quantitative tissue sampling. The major UDP-glucuronosyltransferase (UGT) isoforms involved in the formation of desvenlafaxine-O-glucuronide were also assessed. In vivo human experiments were conducted with healthy volunteers administered desvenlafaxine 100, 300, or 600 mg, followed by 72 hours of plasma sampling. In vitro experiments were conducted with human and animal liver microsomes and human hepatocytes to determine the effect of desvenlafaxine on cytochrome P450 (CYP) enzyme activity. Desvenlafaxine concentrations were measured using high performance liquid chromatography and liquid chromatography/mass spectrometry methods. Results: The primary metabolic pathways for desvenlafaxine included glucuronidation, oxidation, and N-demethylation. In humans, desvenlafaxine was the predominant drug-related species in plasma and urine. However, in mice, rats, and dogs, desvenlafaxine-O-glucuronide was the most commonly detected in plasma and urine. Urine was the primary route of excretion of desvenlafaxine in all species. Multiple UGTs were capable of desvenlafaxine metabolism. Oxidative metabolism via the CYP3A4 was a minor contributor to desvenlafaxine metabolism; however, desvenlafaxine did not induce or inhibit CYP3A4 activity. Desvenlafaxine did not act as a significant mechanism-based inhibitor of the assessed CYP isoenzymes. Conclusion: These findings support other study results suggesting that desvenlafaxine has a simple metabolic profile. Desvenlafaxine is unlikely to contribute to clinically significant CYP-mediated drug-drug interactions. The relatively simple metabolic profile of desvenlafaxine may lead to clinical benefits in those patients being treated for major depressive disorder.