TY - JOUR T1 - Gestation time-dependent pharmacokinetics of intravenous (+)-methamphetamine and (+)-amphetamine in rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.039446 SP - dmd.111.039446 AU - Sarah J. White AU - Elizabeth M. Laurenzana AU - Howard P. Hendrickson AU - William Brooks Gentry AU - Samuel Michael Owens Y1 - 2011/06/01 UR - http://dmd.aspetjournals.org/content/early/2011/06/01/dmd.111.039446.abstract N2 - 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 iv 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 non-renal clearance). The terminal elimination half-life (t1/2λz) of METH and (+)-amphetamine (AMP, a pharmacologically active metabolite of METH) were not different on GD7, but by GD21 AMP t1/2λz was 37% longer than METH t1/2λz (p<0.05). To identify the mechanism for AMP metabolite changes, iv AMP pharmacokinetics on GD21 were compared to AMP metabolite pharmacokinetics following iv METH. The iv AMP t1/2λz was significantly shorter than metabolite AMP t1/2λz (p<0.05), which suggested AMP metabolite formation (not elimination) was a rate-limiting process. To understand the medical consequence of METH use during late-stage pregnancy, timed-pregnant rats received an iv-dose of saline or METH (1, 3 or 5.6 mg/kg) on GD21, 0-2 days antepartum. Even though one rat died and another had stillbirths at term following the 5.6 mg/kg dose, the pharmacokinetic values for all of the other animals were not significantly different. In conclusion, these data showed late-gestational phase reductions in non-renal and renal clearance appear to increase and lengthen METH and AMP exposure in near-term pregnant rats, which could increase susceptibility to METH-induced adverse effects. ER -