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 (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, intravenous AMP pharmacokinetics on GD21 were compared with AMP metabolite pharmacokinetics after intravenous METH. The intravenous AMP t1/2λz was significantly shorter than metabolite AMP t1/2λz (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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA07610]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-EA07310]; the National Institutes of Health National Center for Research Resources [Grant UL1-RR029884]; and a graduate fellowship from GlaxoSmithKline.
S.M.O. and W.B.G. have financial interests in and serve as Chief Scientific Officer and Chief Medical Officer, respectively, of InterveXion Therapeutics LLC (Little Rock, AR), a pharmaceutical biotechnology company focused on treating human drug addiction with antibody-based therapy.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039446.
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ABBREVIATIONS:
- METH
- (+)-methamphetamine
- ANOVA
- analysis of variance
- AMP
- (+)-amphetamine
- AUC0∞
- area under the serum concentration-versus-time curve from time zero to infinity
- ClNR
- nonrenal clearance
- ClR
- renal clearance
- ClT
- total body clearance
- Cl/F
- systemic clearance corrected for bioavailability
- GD
- gestation day
- fm
- fraction of parent drug converted to a metabolite
- fu
- fraction of unchanged parent drug in urine
- GD
- gestational day
- λz
- terminal elimination rate constant
- LC
- liquid chromatography
- LLE
- liquid-liquid phase extraction
- MRT
- mean residence time
- PND
- postnatal day
- t1/2λz
- terminal elimination half-life
- Vd
- volume of distribution
- Vdss
- volume of distribution at steady state.
- Received March 18, 2011.
- Accepted June 1, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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