Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

Milesi-Hallé, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Owens, S. Michael

doi:10.1016/j.taap.2005.04.007

Cited by 85 publications

(78 citation statements)

References 34 publications

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“…The characteristics of AMP elimination following a single METH dose in the rat have also been reported by several investigators (Byrnes-Blake et al 2003;Cho et al 2001;Milesi-Halle et al 2005;Riviere et al 2000). Milesi-Halle et al have reported a much lower AMP to METH ratio in the male and female rat following a 1 mg/kg IV dose (i.e., 0.29 and 0.22) when compared to the pigeon (i.e., 0.47 with an IV dose) (Milesi-Halle et al 2005). The C max for AMP was higher in the pigeon (35 ng/ml) relative to the rat (15 ng/ml) suggesting that AMP might contribute to the behavioral affects observed in the pigeon to a greater extent than possible in the rat.…”

Section: Discussionsupporting

confidence: 69%

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Hendrickson

Hardwick

McMillan

et al. 2008

Pharmacology Biochemistry and Behavior

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Pigeons are used frequently as subjects in behavioral pharmacology research. An advantage of the pigeon is an exceedingly vascular breast muscle, which is easily accessible for injections. The purpose of these studies was to provide a profile of the pharmacokinetics of (+)-methamphetamine (METH) and (+)-amphetamine (AMP), a pharmacologically active metabolite, in pigeons (n = 6) after intramuscular (IM) and intravenous (IV) dosing (0.8 mg/kg). LC-MS/MS analysis was used to determine serum concentrations of METH and AMP. A modified crossover design was used to determine the bioavailability, time to maximum concentration, total clearance, the volume of distribution, the maximal concentration, the area under the concentration-time curve (AUC), and terminal elimination half-life for METH. The route of administration did not significantly affect these pharmacokinetic parameters. The time to maximum concentration for METH and AMP following IM administration was 0.3 h. Maximum AMP serum concentrations were achieved in 2 h, irrespective of the route of administration, and these concentrations remained essentially constant for an additional 6 h. The metabolism of METH to AMP was not affected by the route of administration, and the molar ratio AMP to METH AUC values were the same (IV=0.57; IM=0.41). These results show that METH pharmacokinetics after IM administration in the pigeon are similar to IV administration. Thus IM is a reasonable route of administration for METH behavioral assays in the pigeon if sufficient time for absorption is given following the dose, and the behavioral endpoint is not dependent on the rapid input of METH following an IV dose.

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Section: Discussionsupporting

confidence: 69%

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Hendrickson

Hardwick

McMillan

et al. 2008

Pharmacology Biochemistry and Behavior

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“…Specifically, studies in male rats show anti-drug immunotherapy substantially lowers brain concentrations for a longer period of time than the duration of PCP-or METH-induced behavioral activity Byrnes-Blake et al, 2003). Because the major METH-induced behavioral effects at this METH dose are over in 2-3 hours in female rats (Milesi-Hallé et al, 2005), the re-equilibration of METH brain concentrations back to the low control levels 4.5 hours after antibody treatment would not be expected to produce detectable pharmacological effects. These data also suggest the METH and AMP are cleared from the rats even in the presence of antibody.…”

Section: Downloaded Frommentioning

confidence: 97%

“…By the first time point of brain tissue collection (40 minutes after METH dosing), the METH distribution phase in serum and brain samples appeared complete in both dams and fetuses, and only the terminal elimination phase remained. Due to slower formation and subsequent distribution (Milesi-Hallé et al, 2005;Cohen et al, 2007), AMP did not achieve the linear terminal elimination phase until about 2 hours after METH administration. Table 2 shows the t 1/2 values for the maternal and fetal sera and brain tissues calculated from the data shown in Fig.…”

Section: Meth and Amp Pharmacokinetic Profile In Pregnant Ratsmentioning

confidence: 99%

“…The optimal time for vehicle and mAb4G9 treatments was based on previous studies in male and nonpregnant female rats, which show METH-induced locomotor activity (and AMP serum concentrations) is maximal approximately 30 minutes after a 1 mg/kg i.v. METH dose (Milesi-Hallé et al, 2005). The major METH-induced behavioral effects are over in 2-3 hours (Milesi-Hallé et al, 2005), so a 5-hour final sampling time was after the observable METH pharmacological effects in dams.…”

Section: Experimental Designmentioning

confidence: 99%

“…METH dose (Milesi-Hallé et al, 2005). The major METH-induced behavioral effects are over in 2-3 hours (Milesi-Hallé et al, 2005), so a 5-hour final sampling time was after the observable METH pharmacological effects in dams.…”

Section: Experimental Designmentioning

confidence: 99%

See 2 more Smart Citations

Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

et al. 2014

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We hypothesized that treatment of pregnant rat dams with a dual reactive monoclonal antibody (mAb4G9) against (+)-methamphetamine [METH; equilibrium dissociation rate constant (K D ) = 16 nM] and (+)-amphetamine (AMP; K D = 102 nM) could confer maternal and fetal protection from brain accumulation of both drugs of abuse. To test this hypothesis, pregnant Sprague-Dawley rats (on gestational day 21) received a 1 mg/kg i.v. METH dose, followed 30 minutes later by vehicle or mAb4G9 treatment. The mAb4G9 dose was 0.56 mole-equivalent in binding sites to the METH body burden. Pharmacokinetic analysis showed baseline METH and AMP elimination half-lives were congruent in dams and fetuses, but the METH volume of distribution in dams was nearly double the fetal values. The METH and AMP area under the serum concentration-versus-time curves from 40 minutes to 5 hours after mAb4G9 treatment increased >7000% and 2000%, respectively, in dams. Fetal METH serum did not change, but AMP decreased 23%. The increased METH and AMP concentrations in maternal serum resulted from significant increases in mAb4G9 binding. Protein binding changed from ∼15% to > 90% for METH and AMP. Fetal serum protein binding appeared to gradually increase, but the absolute fraction bound was trivial compared with the dams. mAb4G9 treatment significantly reduced METH and AMP brain values by 66% and 45% in dams and 44% and 46% in fetuses (P < 0.05), respectively. These results show anti-METH/AMP mAb4G9 therapy in dams can offer maternal and fetal brain protection from the potentially harmful effects of METH and AMP.

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Sex Differences in Psychosis: Focus on Animal Models

Gogos

Buuse

2022

Current Topics in Behavioral Neurosciences

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Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

Cited by 85 publications

References 34 publications

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

Sex Differences in Psychosis: Focus on Animal Models

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