title: Gestation time-dependent pharmacokinetics of intravenous (+)-methamphetamine in rats.
abstract: We tested the hypothesis that differences in (+)-methamphetamine (METH) disposition during late rat pregnancy could lead to increased vulnerability to acute METH effects. The disposition of a single 1 mg/kg i.v. METH dose was studied during early (gestation day 7, GD7) and late (GD21) gestation. Results showed gestation time-dependent pharmacokinetics, characterized by a significantly higher area under the METH serum concentration versus time curve and a lower clearance on GD21 (p < 0.05; total, renal, and nonrenal clearance). The terminal elimination half-life (t(1/2λz)) of METH and (+)-amphetamine (AMP; a pharmacologically active metabolite of METH) were not different on GD7, but by GD21, AMP t(1/2λz) was 37% longer than METH t(1/2λz) (p < 0.05). To identify the mechanism for AMP metabolite changes, intravenous AMP pharmacokinetics on GD21 were compared with AMP metabolite pharmacokinetics after intravenous METH. The intravenous AMP t(1/2λz) was significantly shorter than metabolite AMP t(1/2λz) (p < 0.05), which suggested AMP metabolite formation (not elimination) was the rate-limiting process. To understand the medical consequence of METH use during late-stage pregnancy, timed-pregnant rats received an intravenous dose of saline or METH (1, 3, or 5.6 mg/kg) on GD21, 0 to 2 days antepartum. Although one rat died and another had stillbirths at term after the 5.6-mg/kg dose, the pharmacokinetic values for all of the other animals were not significantly different. In conclusion, late-gestational clearance reductions lengthen METH exposure time, possibly increasing susceptibility to adverse effects, including death.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: White
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Laurenzana
authors.forename: Howard
authors.initials: H
authors.lastname: Hendrickson
authors.forename: W Brooks
authors.initials: WB
authors.lastname: Gentry
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006207:Half-Life; D007275:Injections, Intravenous; D008694:Methamphetamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008694:Methamphetamine; D000661:Amphetamine