PT - JOURNAL ARTICLE AU - Esa Meririnne AU - Satu Ellermaa AU - Aino Kankaanpää AU - Ali Bardy AU - Timo Seppälä TI - Pharmacokinetics and Tissue Distribution of the Stereoisomers of 4-Methylaminorex in the Rat AID - 10.1124/jpet.103.060053 DP - 2004 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1198--1205 VI - 309 IP - 3 4099 - http://jpet.aspetjournals.org/content/309/3/1198.short 4100 - http://jpet.aspetjournals.org/content/309/3/1198.full SO - J Pharmacol Exp Ther2004 Jun 01; 309 AB - 4-Methylaminorex, a potential psychostimulant drug of abuse, exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R, which were shown previously to possess stereospecific effects. This study characterized their pharmacokinetic and tissue distribution profiles, and metabolic turnover to norephedrine and norpseudoephedrine, in male Wistar rats. The rats received each isomer intravenously, intraperitoneally, or orally, followed by blood sample collection via cannula (pharmacokinetic study), or tissue sample collection at predetermined time points (tissue distribution study). The samples were analyzed for cis- and trans-isomers, and when appropriate for norephedrine and norpseudoephedrine, with gas chromatography/mass spectrometry. Trans-4S,5S-, cis-4R,5S-, and cis-4S,5R-isomers behaved comparably kinetically (volume of distribution 1.7-2.3 l/kg, distribution half-life 3.8-7.0 min, elimination half-life 35-42 min, and bioavailability 32-57% intraperitoneally or 4-16% orally), whereas trans-4R,5R-isomer differed from the others, with a longer elimination half-life (118-169 min) and higher bioavailability (100% intraperitoneally or 83% orally). The highest isomer concentrations were observed in the kidney followed most frequently by the liver, brain, muscle, and last by fat and blood. The elimination half-lives of the stereoisomers from the tissues were generally similar to those in blood. No pharmacologically significant amounts of norephedrine or norpseudoephedrine were detected in blood or the brain. In conclusion, differences between the stereoisomers of 4-methylaminorex in the pharmacokinetics and tissue distribution are described. However, these differences are not compatible with, and thus may not account for, the distinct behavioral and neurochemical effects of the stereoisomers demonstrated previously. Furthermore, metabolic turnover to norephedrine and norpseudoephedrine does not seem to contribute significantly to 4-methylaminorex pharmacology. The American Society for Pharmacology and Experimental Therapeutics