Vulnerability to (+)-methamphetamine effects and the relationship to drug disposition in pregnant rats during chronic infusion.
Chronic (+)-methamphetamine (METH) use during pregnancy increases the health risk for both mother and fetus. To provide insights into these risks, the relationship between changes in METH disposition and METH-induced pharmacological effects were studied in Sprague-Dawley rat dams and litters. Timed-pregnant rats (n = 5-6) were given saline or METH (5.6-17.8 mg/kg/day) by continuous sc infusion from gestational day (GD) 7 (before organogenesis) until GD21 (0-2 days before delivery). By GD11, all rats in the 17.8-mg/kg/day group died or were sacrificed for humane reasons. There were significant (p < 0.05) dose- and gestational time-dependent decreases in maternal body weight in the 10- to 13.2-mg/kg/day groups, which slowly recovered to near normal by GD21. Continued METH dosing in the surviving groups did not affect the mean pups/litter weight at the end of the experiment on GD21. While maternal and fetal METH and (+)-amphetamine serum concentrations were similar on GD21, brain concentrations were significantly greater in the dams (p < 0.05). Importantly, brain-to-serum ratios in the dams were 9:1 and 3:1 in the pups. METH systemic clearance (Cl(S)) in dams significantly (p < 0.05) decreased from 52 +/- 14 ml/min/kg on GD10 to 28 +/- 6 ml/min/kg on GD21 in all dose groups, indicating late-gestational stage reductions in METH Cl(S). Overall, these findings suggest that there were two periods of increased susceptibility for dams and fetuses during chronic METH treatment. First was the period after the start of METH dosing in which neuroadaptation and tolerance to METH occurs in the adult. The second was at the end of pregnancy when METH clearance was significantly reduced.
White
Sarah J
SJ
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Laurenzana
Elizabeth M
EM
Gentry
William Brooks
WB
Hendrickson
Howard P
HP
Williams
David Keith
DK
Ward
Keith W
KW
Owens
Samuel Michael
SM
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D005865:Gestational Age; D007262:Infusions, Intravenous; D008694:Methamphetamine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects
D001798:Blood Proteins; D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D003913:Dextroamphetamine