Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Abstract

Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug-drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n 5 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography-tandem mass spectrometry assays. Time-dependent, elimination rate-limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and C max ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S-versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steadystate pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300-312 hours) from 185 to 37,447 nM×h] and elimination [terminal half-life of approximately 7-46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion's effects and DDIs with CYP2D6.

Simultaneous Quantitative Determination of Bupropion and its Metabolites by High Performance Liquid Chromatography Tandem Mass Spectrometry Detection: Application to Bioequivalence Study

“…Reported C max based on Bupropion hydrochloride 100 mg tablets for BPR, HBPR and THBPR are 136.2 ng/ml, 269.0 ng/ml and 88.8 ng/ml, respectively. Literature reveals that HPLC methods for plasma, [1][2][3][4] stability method for plasma, 5 metabolite characterization, [6][7] LC-MS methods for human plasma [8][9][10][11][12][13] and rat plasma, 14 pharmacokinetics analysis in human or rat plasma [15][16][17][18][19][20][21][22][23][24] for bupropion and/its metabolite(s) and LC-MS methods for bupropion with combination [25][26][27] are reported. It is noted that reported HPLC methods are not sensitive for the quantification in terminal plasma concentration of bupropion and/or metabolites.…”

Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers

“…Quantifying S-bupropion hydroxylation was thought to improve bupropion utility as an in vivo CYP2B6 probe (27). However, substantial presystemic elimination (i.e., hepatic first pass) of S-bupropion by carbonyl reductases coupled with the complex disposition of (S,S)-hydroxybupropion was recently shown to compromise S-bupropion as a useful probe (25,26).…”

“…The hydroxylation of bupropion, predominantly catalyzed by CYP2B6 (18), was an early and frequently used in vitro and in vivo probe of CYP2B6 activity (19). However, its usefulness in vivo to quantitatively assess induction of drug interactions (20) and to phenotype genetic variants of CYP2B6 (21) has been limited due to the significant competition from non-CYP2B6 parallel elimination pathways (22,23) and the complex disposition of bupropion and 4-hydroxybupropion (24)(25)(26). Quantifying S-bupropion hydroxylation was thought to improve bupropion utility as an in vivo CYP2B6 probe (27).…”

Misidentification of Bupropion Glucuronide Metabolites and Re-evaluation of Metabolite Pharmacokinetics

“…Additionally, UDP-glucuronosyl transferase enzyme kinetics was assessed by incubations of racemic parent aglycones (threohydrobupropion and erythrohydrobupropion) in human liver microsomes. In addition, following the administration of bupropion to healthy volunteers, glucuronide metabolites were quantified in urine, and their urinary excretion kinetics was evaluated.We also read with interest the recent article by Masters et al (2016). Healthy volunteers were administered oral immediate-release racemic bupropion, and the urinary excretion of the parent drug and metabolites was quantified by liquid chromatography-mass spectrometry.…”

“…We also read with interest the recent article by Masters et al (2016). Healthy volunteers were administered oral immediate-release racemic bupropion, and the urinary excretion of the parent drug and metabolites was quantified by liquid chromatography-mass spectrometry.…”