Metabolism of bupropion by baboon hepatic and placental microsomes

Abstract

The aim of this investigation was to determine the biotransformation of bupropion by baboon hepatic and placental microsomes, identify the enzyme(s) catalyzing the reaction(s) and determine its kinetics. Bupropion was metabolized by baboon hepatic and placental microsomes to hydroxybupropion (OH-BUP), threo- (TB) and erythrohydrobupropion (EB). OH-bupropion was the major metabolite formed by hepatic microsomes (Km 36 ± 6 µM, Vmax 258 ± 32 pmol mg protein−1 min−1), however the formation of OH-BUP by placental microsomes was below the limit of quantification. The apparent Km values of bupropion for the formation of TB and EB by hepatic and placental microsomes were similar. The selective inhibitors of CYP2B6 (ticlopidine and phencyclidine) and monoclonal antibodies raised against human CYP2B6 isozyme caused 80% inhibition of OH-BUP formation by baboon hepatic microsomes. The chemical inhibitors of aldo-keto reductases (flufenamic acid), carbonyl reductases (menadione), and 11β-hydroxysteroid dehydrogenases (18β-glycyrrhetinic acid) significantly decreased the formation of TB and EB by hepatic and placental microsomes. Data indicate that CYP2B of baboon hepatic microsomes is responsible for biotransformation of bupropion to OH-BUP, while hepatic and placental short chain dehydrogenases/reductases and to a lesser extent aldo-keto reductases are responsible for the reduction of bupropion to TB and EB.

Metabolism and Disposition of Bupropion in Pregnant Baboons (Papio cynocephalus)

“…On the other hand, in human and baboon placental microsomes, the main metabolites formed were TB and EB. Furthermore, 11b-hydroxysteroid dehydrogenases were identified as the major carbonyl-reducing enzymes responsible for the reduction of BUP to TB and EB in human and baboon microsomal fractions (Wang et al, , 2011. These data support, in part, the use of baboons to study BUP disposition during pregnancy.…”

“…The major metabolite determined in the baboons' plasma was OH-BUP. Previously we reported that in baboons CYP2B was the major hepatic enzyme responsible for the hydroxylation of BUP in vitro (Wang et al, 2011). Following intravenous administration of 1 mg/kg of BUP, the peak plasma concentration of OH-BUP in nonpregnant baboons was ;3-fold less than the peak level of the parent drug.…”

“…The transplacental transfer of BUP and its metabolites also contributes to the total CL of BUP from maternal plasma, as BUP, OH-BUP, TB, and EB were all detected in neonatal plasma after delivery. Based on previous in vitro data, the metabolism of BUP to TB and EB within baboon placenta is expected to be only a minor factor affecting the overall CL of BUP (Wang et al, 2011).…”

“…Furthermore, recent in vitro data obtained in our laboratory revealed similarities between baboons and humans in the biotransformation of BUP by both hepatic and placental microsomes (Wang et al, , 2011. The major metabolites formed by human and baboon hepatic and placental microsomes were hydroxybupropion (OH-BUP), threohydrobupropion (TB), and erythrohydrobupropion (EB).…”

“…The major metabolites formed by human and baboon hepatic and placental microsomes were hydroxybupropion (OH-BUP), threohydrobupropion (TB), and erythrohydrobupropion (EB). OH-BUP was the main metabolite formed by human and baboon hepatic microsomes, and hydroxylation of BUP was catalyzed by CYP2B6 and CYP2B, respectively (Hesse et al, 2000;Wang et al, 2011). On the other hand, in human and baboon placental microsomes, the main metabolites formed were TB and EB.…”