Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

Kharasch, Evan D.; Neiner, Alicia; Kraus, Kristin; Blood, Jane; Stevens, Angela; Miller, John P.; Lenze, Eric J.

doi:10.1002/cpt.1888

Cited by 3 publications

(12 citation statements)

References 40 publications

(183 reference statements)

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“…These findings are consistent with previous data in pregnant women, indicating that racemic BUP disposition is unaltered during pregnancy. 31 Overall, the concentrations of BUP and its metabolites measured postpartum were similar (means within about 40% of each other) to concentrations measured in healthy volunteers at steady-state, 40 supporting the assumption of this study that single time point plasma concentrations reflect the average steady-state concentrations. Similarly, the relative exposures of the metabolites in relation to BUP were consistent with previous studies.…”

Section: Discussionsupporting

confidence: 71%

“…Previous studies in nonpregnant subjects have found R,R-OH-BUP concentrations 40–65 fold higher than S,S-OH-BUP. 16,17,40 It is possible that the smaller difference between S,S-OH-BUP and R,R-OH-BUP concentrations observed in this study reflects differences between patients and healthy volunteers or differences in formulations used and absorption kinetics and should be explored further. This is an important finding as S,S-OH-BUP has been shown to be more effective in improvement of depression, and antagonism of acute nicotine effects, in mouse models.…”

Section: Discussionmentioning

confidence: 94%

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Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites

Fay

Czuba

Sager

et al. 2021

Therapeutic Drug Monitoring

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Background: Bupropion (BUP) is a chiral antidepressant and smoking cessation aide with benefits and side effects correlated with parent and active metabolite concentrations. BUP is metabolized by CYP2B6, CYP2C19, and CYP3A4 to hydroxy-BUP (OH-BUP) as well as by 11b-hydroxysteroid dehydrogenase-1 and aldo-keto reductases to threohydrobupropion (Threo) and erythrohydrobupropion (Erythro), respectively. As pregnancy alters the activity of drugmetabolizing enzymes, the authors hypothesized that BUP metabolism and BUP metabolite concentrations would be altered during pregnancy, potentially affecting the efficacy and safety of BUP in pregnant women.Methods: Pregnant women (n = 8) taking BUP chronically were enrolled, and steady-state plasma samples and dosing interval urine samples were collected during pregnancy and postpartum. Maternal and umbilical cord venous blood samples were collected at delivery from 3 subjects, and cord blood/maternal plasma concentration ratios were calculated. The concentrations of BUP stereoisomers and their metabolites were measured. Paired t tests were used to compare pharmacokinetic parameters during pregnancy and postpartum.Results: No significant changes were observed in the steady-state plasma concentrations, metabolite to parent ratios, formation clear-ances, or renal clearance of any of the compounds during pregnancy when compared with postpartum. The umbilical cord venous plasma concentrations of BUP and its metabolites were 30%-60% lower than maternal plasma concentrations.Conclusions: This study showed that there are no clinically meaningful differences in the stereoselective disposition of BUP or its metabolites during pregnancy, indicating that dose adjustment during pregnancy may not be necessary. The results also showed that the placenta provides a partial barrier for bupropion and its metabolite distribution to the fetus, with possible placental efflux transport of bupropion and its metabolites.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 94%

Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites

Fay

Czuba

Sager

et al. 2021

Therapeutic Drug Monitoring

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“…CYP2B6 exclusively catalyzes 4-hydroxylation of racemic BUP and its enantiomers in vitro (Faucette et al, 2000;Coles and Kharasch, 2008) and in vivo (Benowitz et al, 2013;Kharasch and Crafford, 2019). However, the extent of stereoselectivity observed in the present study and the literature cannot fully explain the marked difference in the disposition of SS-versus RR-OHBUP observed clinically (Masters et al, 2016a;Kharasch et al, 2020), suggesting mechanisms other than CYP2B6 [e.g., subsequent metabolism (Gufford et al, 2016) or renal excretion (Masters et al, 2016a)] of SS-versus RR-OHBUP may explain clinically observed disposition of OHBUP diastereomers. Higher Cl int for the reduction of BUP to SS-THBUP (42.1-and 19.2-fold) was observed in HLMs and HLS9 fractions, respectively, compared to the Cl int for the formation of RR-THBUP.…”

Section: Discussionmentioning

confidence: 52%

“…Marked stereoselective disposition of BUP and its active metabolites has been observed clinically (Masters et al, 2016a;Kharasch et al, 2020). Yet, understanding of in vitro stereoselective metabolism of BUP remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine

Bamfo

Desta

2022

Drug Metab Dispos

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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 (Cl int ) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions and HLCs, respectively; Cl int for the formation of SS-OHBUP and RS-EHBUP were also higher (2.7to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, ≥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 This article has not been copyedited and formatted. The final version may differ from this version.

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“…Bupropion is FDA-approved for treating major depressive disorder, seasonal affective disorder, and aiding smoking cessation in adults, alone or in combination with other drugs (Patel et al, 2016;Hajizadeh et al, 2023). It is also used for obesity, cocaine or amphetamine abuse, sexual dysfunction, and chronic pain in adults and attention-deficit/hyperactivity disorder in adults and children (Kharasch et al, 2020). Bupropion is available in immediate-, sustainedand extended-release oral formulations.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion

Kharasch,

Lenze

2024

Drug Metab Dispos

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Bupropion is used for treating depression, obesity, seasonal affective disorder, and for smoking cessation.Bupropion is commonly-prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in CYP2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes.

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Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

Cited by 3 publications

References 40 publications

Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites

Pregnancy Has No Clinically Significant Effect on the Pharmacokinetics of Bupropion or Its Metabolites

Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion

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