Posted by chemist on April 25, 2005, at 20:31:02
In reply to Re: Effects of Selegiline's amphetamine metabolite » chemist, posted by cache-monkey on April 25, 2005, at 13:52:05
> > hello there, chemist here...bupropion is a major substrate of the cyp-2B6 isoenzyme, and a weak inhibitor of 2D6. the 3 active metabolites are reported to exhibit activities rangin from 20% to 50% or the parent compound. the drug does not inhibit its own metabolism, nor does it autoinduce. the majority of drugs are metabolized (those that go the hepatic route) by the 2D6 isoenzyme, and if you are caucasian, there is a 7 to 10% chance your are a poor-metabolizer in re: the 2D6. the metabolic route for bupropion is via phase I, and the hydroxy derivative is half as active as the parent and, further, is metabolized by the 2B6 (not 2D6). given the large difference in K_{i}, it is unlikely though possible that some competitive binding is at play, although a more reasonable scenario is that use of another drug with similar affinity for 2B6 - paroxetine, sertraline, theophylline etc. - is responsible for increased serum concentration of the parent and the adverse effects associated with the increase...all the best, chemist
> >
>
> Hi chemist,
>
> Thanks for chiming in here. I've read in a couple of places [eg: 1,2] that hydroxybupropion (HB) is or could be a substrate of 2D6.
>
> Further, according to a recent article in Molecular Pharmacology [3]: "bupropion is extensively metabolized to (2S,3R)- and (2S,3S)-hydroxybupropion ... . The concentrations of hydroxybupropion isomers present in cerebrospinal fluid are six times greater than those of the parent bupropion ... . Although it has weak NE-uptake properties, the high levels of the metabolite in brain may be sufficient to produce clinically meaningful blockade of NE reuptake and thereby account for much of the drug's activity. Indeed, plasma levels of hydroxybupropion greatly exceed those of the parent drug, reaching 10 to 100 times the concentration of bupropion ... ."
>
> The authors go on to characterize the affinities of bupropion and the HB metabolites, yielding:
> ===========================================================
> Values given are mean ± S.D., IC50s reported in nM
>
> drug..............[3H]DA.........[3H]NE
>
> Bupropion.........550 ± 65.......1900 ± 12
> (2S,3S)-HB........790 ± 11.......520 ± 35
> (2R,3R)-HB........>10,000........>10,000
> ===========================================================
> source: [3]
>
> Consequently, in steady state the NE effects of HB are likely to dominate the DA effects of BUP+HB. This is potentially bad for people like me (and possibly Sarah T?) who don't like ther NE system to be trucked with. There also seems to be significant inter-individual variation in the ratio of HB to BUP [2]. Finally, adding on a poor CYP-2D6 metabolic status, and the reaction is worse.
>
> Best,
> cache-monkey
>
> 1. http://www.postgradmed.com/issues/1999/11_99/cadieux.htm
> 2. Pollock BG, Sweet RA, Kirschner M, Reyolds CF. "Bupropion plasma levels and CYP2D6 phenotype." Ther Drug Monit 1996; 18:581-585.
> 3. M. Imad Damaj, F. Ivy Carroll, J. Brek Eaton, Hernan A. Navarro, Bruce E. Blough, Sadiq Mirza, Ronald J. Lukas, and Billy R. Martin. "Enantioselective Effects of Hydroxy Metabolites of Bupropion on Behavior and on Function of Monoamine Transporters and Nicotinic Receptors." Mol Pharmacol 2004 66: 675-682.hello there, chemist here...please pardon my jumping in on your thread...the question i have in mind is what you address in noting the selectivity for the diastereomeric pairs (ref [3])...the IC50 values for the (2S,3S) and (2S,3R) HB metabolites in the mol. pharm. article are striking, yet mimic what we see with alpha4beta2 and alpha7 nAChR specificity for nicotine and derivatives (they ``like'' (S)). given the stereospecificity of (excuse my lapse in enzymology here and elsewhere!) almost all enzymes we have categorized, is it likely that your HB diastereomers are ``victims'' of induced fit for the 2D6 after the tert-butyl group is removed? this does leave a nitrogen that is attractive to 2D6, while the bulk of the t-butyl is absent...assuming the beta-hydroxylation is followed by a leaving t-butyl and demethylation, we are looking at something darned close to epi...your thoughts and guidance requested, if you please, as i ought to be set straight and am in the dark at the moment.....thanks much, and all the best, chemist
poster:chemist
thread:487473
URL: http://www.dr-bob.org/babble/20050423/msgs/489453.html