Bupropion - Pharmacokinetics

Pharmacokinetics

Bupropion is metabolized in the liver.

It has several active metabolites: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites are presented in Table 1. Bupropion is known to weakly inhibit the α₁ adrenergic receptor, with a 14% potency of its dopamine uptake inhibition, and the H₁ receptor, with a 9% potency.

The biological activity of bupropion can be attributed to a significant degree to its active metabolites, in particular to S,S-hydroxybupropion. GlaxoSmithKline developed this metabolite as a separate drug called radafaxine, but discontinued development in 2006 due to "an unfavourable risk/benefit assessment".

Bupropion is metabolized to hydroxybupropion by CYP2B6, an isoenzyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. The mechanism of formation of erythro-hydrobupropion and threo-hydrobupropion has not been studied but is probably mediated by one of the carbonyl reductase enzymes. The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (and the half-life from 3 to 16 hours), and of hydroxybupropion by as much as 7.5 times (and the half-life from 12 to 38 hours). Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.

There are significant interspecies differences in the metabolism of bupropion, with guinea pigs' metabolism of the drug being closest to that of humans compared to mice and rats. Particular caution is needed when extrapolating the results of experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.

There have been two reported cases of false-positive urine amphetamine tests in persons taking bupropion. As substituted phenethylamines encompass the substituted amphetamines where bupropion is described as β-Keto-3-chloro-N-tert-butylamphetamine, this is likely the cause of a positive result shown in drug-screening tests on those taking the medicine. More specific follow-up tests were negative.