pH dependent efflux of methamphetamine derivatives and their reversal through human Caco-2 cell monolayers.
The purpose of this study was to investigate possible efflux mechanisms involved in amphetamine derivative transport such as for 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), para-methoxyamphetamine (p-MA), dexamphetamine and pseudoephedrine, especially across pH gradients that exist in intestinal or kidney transport. This was determined using our Caco-2 subclone, CLEFF9. Transport of the amphetamine derivatives was evaluated at pH 7.4 and pH 6/7.4+/-efflux inhibitors. Na+-H+ transporter inhibition via carbonyl cyanide-4-trifluoromethoxy phenylhydrazone (FCCP), and metabolic inhibition using Na-azide and Na-orthovanadate were also conducted, as well as using noradrenalin, adrenalin and other inhibitors of a range of carrier mediated transport systems such as histamine, organic cation transporters and dopamine carrier systems. At pH 7.4, the rate of transport for dexamphetamine, pseudoephedrine and MDMA in both apical to basolateral and reverse directions was all very rapid, confirming extensive passive diffusion at systemic pH. However, creating a pH 6.0/7.4 gradient showed marked increase in basolateral to apical transport of all amphetamines tested, with dexamphetamine, MDEA, MDMA and p-MA having a net efflux ratio of around 16, 14, 13 and 11 respectively and this was not reversed with P-glycoprotein inhibitors. Azide, FCCP, adrenalin, noradrenalin and reserpine were able to reduce the efflux by 2 to 3 fold, although tetraethylammonium could not. This suggested that extraneuronal monoamine transporters (hEMT) could be involved. This data suggests that elevated endogenous adrenalin levels may reduce amphetamine removal from the body based on these in vitro studies. Also, the use of stomach acid lowering drugs could result in more rapid systemic uptake of these amphetamine derivatives.[1]References
- pH dependent efflux of methamphetamine derivatives and their reversal through human Caco-2 cell monolayers. Crowe, A., Diep, S. Eur. J. Pharmacol. (2008) [Pubmed]
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