ToxSci Advance Access published online on June 10, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp127
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Vulnerability to (+)-Methamphetamine Effects and the Relationship to Drug Disposition in Pregnant Rats during Chronic Infusion
* Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205; WhiteSarahJ{at}uams.edu; emlaurenzana{at}gmail.com; mowens{at}uams.edu
Department of Anesthesiology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205; GentryWilliamB{at}uams.edu
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205; HendricksonHowardP{at}uams.edu
Department of Biostatistics, College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205; WilliamsDavidK{at}uams.edu
¶ Global Preclinical Development, Bausch & Lomb, Rochester, NY 14609; Keith_W_Ward{at}bausch.com
Address correspondence to: S. Michael Owens, PhD, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham, #611, Little Rock, AR 72205, mowens{at}uams.edu, Phone: 501-686-5487 Fax: 501-526-4618
Received March 20, 2009; revision received June 3, 2009; accepted June 3, 2009
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Abstract |
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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 GD7 (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 10-13.2 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 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 systemic clearance. Overall, these findings suggest 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.
Key Words: Methamphetamine; pregnancy; rat; drug abuse; pharmacokinetics.