RT Journal Article
SR Electronic
T1 Stereoselective metabolism of bupropion to active metabolites in cellular fractions of human liver and intestine.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2022-000867
DO 10.1124/dmd.122.000867
A1 Bamfo, Nadia O.
A1 Lu, Jessica Bo Li
A1 Desta, Zeruesenay
YR 2022
UL http://dmd.aspetjournals.org/content/early/2022/05/05/dmd.122.000867.abstract
AB Striking stereoselective disposition of the antidepressant and smoking cessation aid bupropion and its active metabolites observed clinically influence patients' response to BUP therapy and its clinically important drug-drug interactions (DDI) with CYP2D6 substrates. However, understanding of the biochemical mechanisms responsible is incomplete. This study comprehensively examined hepatic and extrahepatic stereoselective metabolism of BUP in vitro. Racemic-, R- and S-BUP was incubated separately with pooled cellular fractions of human liver (microsomes, HLMs; S9 fractions, HLS9 fractions; and cytosols, HLCs) and intestinal (microsomes, HIMs; S9 fractions, HIS9 fractions; and cytosols, HICs) and cofactors. Formation of diastereomers of 4-hydroxyBUP (OHBUP), threohydroBUP (THBUP) and erythrohydroBUP (EHBUP) were quantified using a novel chiral UHPLC/MS/MS method. Racemic BUP (but not R- or S-BUP) was found suitable to determine stereoselective metabolism of BUP; both enantiomers showed complete racemization. Compared to that of RR-THBUP, the in vitro intrinsic clearance (Clint) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions and HLCs, respectively; Clint for the formation of SS-OHBUP and RS-EHBUP were also higher (2.7- to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, {greater than or equal to}95% of total reduction was accounted by the formation of RR-THBUP. Ours is the first to demonstrate marked stereoselective reduction of BUP in HLCs, HIMs, HIS9 fractions and HICs, providing the first evidence for tissue- and cellular fraction-dependent stereoselective metabolism of BUP. These data may serve as the first critical step towards understanding factors dictating BUP's stereoselective disposition, effects and DDI risks. Significance Statement This work provides a deeper insight into bupropion stereoselective oxidation and reduction to active metabolites in cellular fractions of human liver and intestine tissue. The results demonstrate tissue- and cellular fraction-dependent stereospecific metabolism of bupropion. These data may improve prediction of bupropion stereoselective disposition and understanding of bupropion’s effects and CYP2D6- dependent drug-drug interaction in vivo.