Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Brandon T GuffordZeruesenay Desta

Abstract

Bupropion is a widely used antidepressant and smoking cessation aid in addition to being one of two US Food and Drug Administration-recommended probe substrates for evaluation of cytochrome P450 2B6 activity. Racemic bupropion undergoes oxidative and reductive metabolism, producing a complex profile of pharmacologically active metabolites with relatively little known about the mechanisms underlying their elimination. A liquid chromatography-tandem mass spectrometry assay was developed to simultaneously separate and detect glucuronide metabolites of (R,R)- and (S,S)-hydroxybupropion, (R,R)- and (S,S)-hydrobupropion (threo) and (S,R)- and (R,S)-hydrobupropion (erythro), in human urine and liver subcellular fractions to begin exploring mechanisms underlying enantioselective metabolism and elimination of bupropion metabolites. Human liver microsomal data revealed marked glucuronidation stereoselectivity [Cl(int), 11.4 versus 4.3 µl/min per milligram for the formation of (R,R)- and (S,S)-hydroxybupropion glucuronide; and Cl(max), 7.7 versus 1.1 µl/min per milligram for the formation of (R,R)- and (S,S)-hydrobupropion glucuronide], in concurrence with observed enantioselective urinary elimination of bupropion glucuronide conjugates. ...Continue Reading

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Citations

Jun 19, 2016·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Aaron M TeitelbaumEvan D Kharasch
Sep 24, 2016·ACS Medicinal Chemistry Letters·Jennifer E SagerNina Isoherranen
Jun 4, 2016·The Journal of Pharmacology and Experimental Therapeutics·Andrea R MastersZeruesenay Desta
Aug 9, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jennifer E SagerNina Isoherranen
Oct 21, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aaron M Teitelbaum, Evan D Kharasch
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