p-hydroxymethamphetamine enantiomer pharmacokinetics and metabolism in rats: Absence of N-demethylation

p-hydroxymethamphetamine (OHMAP) is one of the major metabolites of the widely abused drug methamphetamine (MAP). The demethylation of OHMAP to p- hydroxyamphetamine (OHAP) has been shown in vitro but has never been reported in vivo. The disposition kinetics as well as the metabolism of OHMAP was investigated employing a sensitive HPLC method which can separate the enantiomers of OHMAP and OHAP. Both conjugated and unconjugated forms of these compounds can bc quantitated. Male Sprague Dawley rats were given an iv bolus oF racemic OHMAP (20mgkg^-1) and serum and urine samples were collected at selected times. The serum concentration time data for OH MAP enantiomers could be described by a biexponential equation. Tile clearance of D-OHMAP (93.5mL min^-1 kg -¹) was slightly, but statistically significantly, greater than that of the L-enantiomer (83.9mL min^-1 kg^{- 1}). The steady-state volumes of distribution of L- and D-OHMAP were (mean±SD) 3.15±0.84 and 4.23±1.76L kg^-1 respectively. No significant concentrations or amounts of OHAP enantiomers could he detected in any serum or urine sample. Rats excreted more unchanged L-OHMAP (34%) than D-OHMAP (29%). In contrast, more conjugated D-OHMAP (57%) was recovered compared to the conjugated L-OHMAP (52%). The results suggest that there is slight stereoselectivity in the disposition of OHMAP enantiomers. The N- demethylation product (OHAP) was not produced in vivo.