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Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug.

ABSTRACT: N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbupropion, bupropion and their metabolites in plasma and brain tissue. In separate studies, the prodrug was delivered by intraperitoneal injection (IP) to assess hepatic metabolism and then by oral gavage (PO) to assess the contribution from intestinal enzymes. Bupropion was administered in parallel. The pharmacokinetic profile of bupropion and N-methylbupropion were not comparable when dosed by intraperitoneal injection but when dosed orally, N-methylbupropion showed a comparable bupropion and metabolite PK plasma profile to bupropion. Plasma and brain levels of N-methylbupropion show that it is extensively metabolized to bupropion and its metabolites, and N-methyl-threo-hydrobupropion. This data coupled to the reduced DAT and NET system in vitro activity described in paper 1 would suggest that the N-methyl derivative of bupropion may have potential as an oral prodrug of bupropion in humans.

SUBMITTER: O'Byrne PM

PROVIDER: S-EPMC4078515 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug.

O'Byrne Paul Matthew PM Williams Robert R Walsh John J JJ Gilmer John F JF

Pharmaceuticals (Basel, Switzerland) 20140528 6

N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbuprop ...[more]

PMID: 24878537

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Project description:BackgroundBupropion is a unique class of antidepressant. In overdose, it is associated with tachycardia, altered mental status, and a dose-dependent risk of seizures, which can be delayed. Despite being a common medication, there is a paucity of data comparing toxicity in younger versus older children with bupropion exposures. The primary purpose of this study is to examine bupropion toxicity in pediatric patients and assess for toxicity differences between younger and older (teenaged) groups.MethodsThis single-center, observational cohort study reviewed pediatric patients presenting to a toxicology service between 2011 and 2018. The primary outcome measures evaluated were the presence of any seizure, delayed seizure (defined as occurring at least 6 hours after hospital arrival), and a composite endpoint of seizure, hypotension, or need for endotracheal intubation. Patients were subdivided into two groups-those 12 years and under, compared with those 13-17 years.ResultsA total of 80 unique pediatric cases were identified. Overall, the median (IQR) age was 14 (2.4-16) years. Patients under 13 years accounted for 31 (39%) of cases, whereas the remaining 49 cases were adolescents. Compared with the adolescents, the younger patients were less likely to be female (41.9% vs. 71.4%; p?=?0.009) and more likely to have an unintentional ingestion (100% vs. 10.2%; p?<?0.001). The younger group was more likely to present to health care earlier after the ingestion (median 61 (IQR 39-103) min vs. 139 (67-399) min; p?=?0.002). The older group was more likely to be tachycardic (73.5% vs. 19.4%; p?<?0.001), have sustained tachycardia (71.4% vs. 29% p?<?0.001), and more likely to have altered mental status on arrival (38.8% vs. 6.5%; p?<?0.001). Seizures were also much more likely in the older group (40.8% vs. 3.2%; p?<?0.001). Adolescents were much more likely than younger children to reach the pre-defined composite endpoint (42.9% vs. 6.5%; p <?0.001), but this was largely driven by the seizures.ConclusionBupropion ingestions are relatively common among pediatric patients. However, adolescents are much more likely to present with more severe toxicity. Seizures are uncommon among younger children with exploratory ingestions.

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Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug.

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Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug.

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