Metabolism Studies of Desvenlafaxine

Abstract

Background: This series of experiments was conducted to describe the metabolic profile of the serotoninnorepinephrine 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 [ 14 C]-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.

Reversal of corticosterone-induced BDNF alterations by the natural antioxidant alpha-lipoic acid alone and combined with desvenlafaxine: Emphasis on the neurotrophic hypothesis of depression

“…One hour after DVS administration the animals were given ALA (100 or 200 mg/ kg). The time interval between the administration of DVS and ALA was set at 1 h because a previous study showed that the maximum mean plasma concentration of DVS in mice occurred 1 h after oral administration of the drug (DeMaio et al, 2011). The experimental design is represented in Fig.…”

Psychiatric treatment considerations with direct acting antivirals in hepatitis C

“…In a single study involving telaprevir, escitalopram area under the curve (AUC) was reduced by 35%, suggesting the need for clinicians to monitor the need for dose optimization on triple therapy [50]. No significant DDI has been observed between escitalopram and boceprevir [37].…”

Avaliação da bioequivalência entre duas formulações de succinato de desvenlafaxina monoidratado – 50 mg comprimido revestido de liberação prolongada – administradas em jejum e pós-prandial em voluntários sadios de ambos os sexos

“…Primeiro, as vias de administração foram diferentes (desvenlafaxina -administração oral; dimenidrinato -administração intravenosa). Segundo, a principal via de metabolização da desvenlafaxina é a glucorunização e, em menor extensão, a via oxidativa da isoforma do citocronomo P450 3A4 (DeMaio et al, 2011;Spina et al, 2012)2012, enquanto o metabolismo do dimenidrinato envolve a isoforma CYP2D6 (Takeda, 2009).…”

“…Sobre o metabolismo da desvenlafaxina, a principal via envolvida é a glucuronidação através da UDP-glucuroniltransferase (isoformas UGT1A1, UGT1A3, UGT2B4, UGT2B15 e UGT2B17) e, em menor extensão, através do metabolismo oxidativo (N-desmetilação) pela isoforma do citocromo P450 3A4 (CYP3A4) (DeMaio et al, 2011). Devido a essas características no metabolismo, a desvenlafaxina apresenta vantagens em relação a outros antidepressivos como a venlafaxina (metabolizada extensivamente pela isoforma CYP2D6), pois a interação com outros fármacos é reduzida ou inexistente (Colvard, 2014)"container-title":"Mental Health Clinician","page":"35-39","volume":"4","issue":"1","source":"mhc.cpnp.org (Atypon.…”