title: Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats.
abstract: These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham #611, Little Rock, AR 72205, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Milesi-Hallé
authors.forename: Howard P
authors.initials: HP
authors.lastname: Hendrickson
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Laurenzana
authors.forename: W Brooks
authors.initials: WB
authors.lastname: Gentry
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
mesh_terms: D000661:Amphetamine / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008694:Methamphetamine / Q000378:metabolism / Q000493:pharmacokinetics*; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D021241:Spectrometry, Mass, Electrospray Ionization; D013239:Stereotyped Behavior / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D000661:Amphetamine