Effects of dose and route of administration on pharmacokinetics of (+ or -)-3,4-methylenedioxymethamphetamine in the rat - PubMed (original) (raw)

Comparative Study

. 2009 Nov;37(11):2163-70.

doi: 10.1124/dmd.109.028506. Epub 2009 Aug 13.

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Comparative Study

Effects of dose and route of administration on pharmacokinetics of (+ or -)-3,4-methylenedioxymethamphetamine in the rat

Michael H Baumann et al. Drug Metab Dispos. 2009 Nov.

Abstract

Based on animal data, there is speculation that (+ or -)-3,4-methylenedioxymethamphetamine (MDMA) is neurotoxic to humans. Extrapolation of MDMA findings from animals to humans requires assessment of pharmacokinetics in various species, and low-dose administration data from rats are lacking. In this study, we examine MDMA pharmacokinetics in rats given low (2 mg/kg) and high (10 mg/kg) doses of racemic MDMA via intraperitoneal, subcutaneous, and oral routes. Repeated blood specimens were collected from venous catheters, and plasma was assayed for MDMA and its metabolites, 4-hydroxy-3-methoxymethamphetamine (HMMA) and 3,4-methylenedioxyamphetamine (MDA), by gas chromatography-mass spectrometry. After 2 mg/kg, maximum MDMA concentrations (C(max)) were approximately 200 ng/ml for intraperitoneal and subcutaneous routes, but less for the oral route. MDMA plasma half-lives were <1 h for low-dose groups, whereas HMMA and MDA half-lives were >2 h. After 10 mg/kg, MDMA areas under the curve (AUCs) were 21-fold (intraperitoneal), 10-fold (subcutaneous), and 36-fold (oral) greater than those at 2 mg/kg. In contrast, HMMA AUC values in high-dose groups were <3-fold above those at 2 mg/kg. Several new findings emerge from this report of low-dose MDMA pharmacokinetics in rats. First, 2 mg/kg MDMA in rats can produce MDMA C(max) values similar to those in humans, perhaps explaining why both species discriminate 1.5 mg/kg MDMA in laboratory paradigms. Second, our data provide additional support for nonlinear kinetics of MDMA in rats, and, analogous to humans, this phenomenon appears to involve impaired drug metabolism. Finally, given key similarities between MDMA pharmacokinetics in rats and humans, data from rats may be clinically relevant when appropriate dosing conditions are used.

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Figures

Fig. 1.

Fig. 1.

MDMA metabolism in humans and rats. Thick arrows represent major pathways of biotransformation, and thin arrows indicate minor pathways. The main cytochrome P450 isoforms responsible for specific reactions in humans (H) and rats (R) are noted. COMT, catechol-_O_-methyltransferase.

Fig. 2.

Fig. 2.

Effects of 2 and 10 mg/kg MDMA on 5-HT behavioral syndrome in rats. Rats bearing indwelling jugular catheters received MDMA by the intraperitoneal, subcutaneous, or oral route. Subjects were observed for 1 min immediately before the withdrawal of each blood specimen for the first 5 h after treatment (nine time points). Flattened body posture and forepaw treading were scored as described under Materials and Methods, and rats were given a single summed score for each behavior. Data are the mean ± S.D. for n = 4 to 5 rats/group. *, P < 0.05, compared with intraperitoneal and subcutaneous routes at 2 mg/kg MDMA.

Fig. 3.

Fig. 3.

Time-concentration profiles for plasma MDMA after administration of 2 and 10 mg/kg MDMA by the intraperitoneal, subcutaneous, or oral route. Rats bearing indwelling jugular catheters received MDMA at time 0, and blood specimens (0.25 ml) were withdrawn via catheters at 0.8, 0.16, 0.25, 0.5, 1, 1.5, 2.5, 3.5, 5, 7, and 10 h after treatment. Plasma was assayed for MDMA by GCMS as described under Materials and Methods. Data are mean ± S.D. for n = 4 to 5 rats/group.

Fig. 4.

Fig. 4.

Time-concentration profiles for plasma HMMA after administration of 2 and 10 mg/kg MDMA by the intraperitoneal, subcutaneous, or oral route. Rats bearing indwelling jugular catheters received MDMA at time 0, and blood specimens (0.25 ml) were withdrawn via catheters at 0.8, 0.16, 0.25, 0.5, 1, 1.5, 2.5, 3.5, 5, 7, and 10 h after treatment. Plasma was assayed for HMMA by GCMS as described under Materials and Methods. Data are the mean ± S.D. for n = 4 to 5 rats/group.

Fig. 5.

Fig. 5.

Time-concentration profiles for plasma MDA after administration of 2 and 10 mg/kg MDMA by the intraperitoneal, subcutaneous, or oral route. Rats bearing indwelling jugular catheters received MDMA at time 0, and blood specimens (0.25 ml) were withdrawn via catheters at 0.8, 0.16, 0.25, 0.5, 1, 1.5, 2.5, 3.5, 5, 7, and 10 h after treatment. Plasma was assayed for MDA by GCMS as described under Materials and Methods. Data are the mean ± S.D. for n = 4 to 5 rats/group.

Fig. 6.

Fig. 6.

Effects of 2 and 10 mg/kg MDMA on postmortem tissue concentrations of 5-HT in rat cortex and striatum. Rats bearing indwelling jugular catheters received MDMA by the intraperitoneal, subcutaneous, or oral route. Subjects were returned to the vivarium after blood sampling procedures, and a group of control rats received 1 ml/kg i.p. saline. Two weeks later, all rats were decapitated, brain regions were dissected, and tissue was frozen until 5-HT assay by HPLC-electrochemical detection as described under Materials and Methods. Data are the mean ± S.D. for n = 4 to 5 rats/group expressed as a percentage of the saline-treated control. Tissue concentrations of 5-HT in control rats were 210 ± 52 and 319 ± 77 pg/mg of tissue for cortex and striatum, respectively.

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