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

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Abstract

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague–Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague–Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration–time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.

Introduction

According to the World Drug Report 2000 (United Nations, 2000), over 38 million people abuse amphetamine and its derivatives, exceeding the use of cocaine worldwide. Due in part to its ease of manufacture, (+)-methamphetamine (METH) use is increasing among various age groups, in the United States and around the world. Because of the serious medical problems associated with METH use (Melega et al., 1995) and the lack of specific treatments for adverse effects like overdose or addiction, animal models are needed to help clarify the mechanisms underlying its adverse actions and to optimize the development of treatments for METH abuse.

Using noninvasive imaging techniques, Volkow et al. (2001) found METH-induced motor and cognitive deficits in abstinent METH users. In most cases, however, the acute and chronic effects induced by high METH doses cannot be safely studied in human subjects. Because of ethical, safety, and convenience issues, the male rat is commonly used as an animal model for studying METH effects. Nevertheless, male rats display significant differences in METH pharmacokinetics when compared to humans, even after consideration of species differences (Cho et al., 2001, Rivière et al., 2000).

METH pharmacokinetic studies in humans show the drug has extensive extravascular distribution (volume of distribution = 3.7 l/kg) and a long terminal elimination half-life (t1/2λz ≈ 13 h; Cook et al., 1993). In male rats, METH has a short t1/2λz (about 1 h). Male rats eliminate approximately 53% of a METH dose as the 4-hydroxylated metabolite (Lin et al., 1997). More importantly, male rats form 34–48% of a METH dose as the pharmacologically active metabolite (+)-amphetamine (AMP) vs. only 15% of AMP formed after METH administration to humans (Rivière et al., 1999, Rivière et al., 2000). These data suggest that the greater accumulation of AMP in male rats could lead to a different and overall greater pharmacological profile than that expected in humans. Furthermore, renal elimination of METH in male rats is only about 13% of a METH dose (Rivière et al., 1999), contrary to humans who eliminate about 45% of a METH dose as unchanged drug (Cook et al., 1993). These findings suggest the male rat, although a useful model for METH studies, has important differences from the human metabolic and pharmacokinetic profile, and those differences should be carefully considered when extrapolating results from male rats to humans.

In contrast to male rats, female rats usually clear drugs at a slower rate than males (Kato, 1974, Mugford and Kedderis, 1998), which is typically attributed to differences in the expressed levels of cytochrome P-450 (CYP-450) and other metabolizing enzymes (Kato and Yamazoe, 1992). A differentiated daily pattern of growth hormone release (Furukawa et al., 1999) contributes to different levels of CYP-450 expression in females, influencing their metabolic capability. Sex differences in AMP in vivo metabolism are also reported (Kato, 1974), with male rats showing greater formation of AMP than female rats.

In humans, although one study reports gender differences in METH use (Brecht et al., 2004), reports of gender-related differences in METH effects are contradictory and incomplete. While there are reports of METH pharmacokinetics in men and limited studies in women subjects (Cook et al., 1993, Harris et al., 2003, Schepers et al., 2003), these reports do not adequately determine if gender differences in METH metabolism or pharmacokinetics in humans indeed exist. Possible differential effects in men and women are a potentially important issue considering the increasing number of women abusing METH and the possible health impact on women of childbearing age.

In rats, sex-based differences in behavioral response to amphetamines are reported. Bisagno et al. (2003) report a greater locomotor response to AMP in female Sprague–Dawley rats when compared to male rats. AMP-induced locomotor effects include more intense and longer lasting stereotyped response, as well as greater rotational behavior. Other studies describe sex differences in locomotor activity induced by METH in Wistar rats (Mattei and Carlini, 1996). However, these studies did not explore possible pharmacokinetic mechanisms involved in the sex differences in METH-induced behavior.

The current studies were designed to determine the effects of METH dose and rat sex on the pharmacokinetics and metabolic disposition of METH and its metabolite AMP in male and female Sprague–Dawley rats. We then investigated how pharmacokinetic mechanisms contribute to sex-related differences in METH-induced behavior. These experiments sought to determine whether female rats could offer advantages over male rats as an animal model for better understanding human METH pharmacological effects.

Section snippets

Animals

Male and female Sprague–Dawley rats (Hilltop Lab Animals Inc., Scottsdale, PA), each with two surgically implanted vascular catheters, were used in the pharmacokinetic studies. Rats with one vascular catheter were used in the locomotor activity studies. Animals were housed individually in a light-controlled environment (12-h light/dark cycle). They received water ad libitum and were fed approximately 20 g of food pellets daily, which maintained their body weights between 250 and 280 g (females)

METH pharmacokinetic studies

The excellent sensitivity and precision of our LC/MS/MS analytical method permitted quantitation of low concentrations of METH and its metabolite AMP obtained in the pharmacokinetic studies. Table 1 summarizes the average pharmacokinetic values of METH obtained after 1.0 and 3.0 mg/kg METH doses in male and female rats.

The METH and AMP serum concentration vs. time profiles obtained after a 1.0 and 3.0 mg/kg METH dose are shown in Fig. 1, Fig. 2, respectively. The METH area under the

Discussion

These studies determined the pharmacokinetics and pharmacodynamics of METH and its pharmacologically active metabolite AMP in male and female rats. To accomplish this goal, we characterized the dispositional properties of METH and AMP in male and female rats after a 1.0 and a 3.0 mg/kg METH dose. These doses were chosen because preliminary experiments showed they produce moderate (1.0 mg/kg) to high (3.0 mg/kg) levels of locomotor activity without causing apparent long-lasting toxicity. In

Acknowledgments

The authors thank Melinda Gunnell, Yingni Che, Jeremy West, and Sherri Wood for their excellent technical assistance. This work was supported by NIDA grants P01 DA14361, R01 DA11560, and NSF EPS-9977816 (to S.M.O.), K25 DA14601 (to H.P.H.), and a GlaxoSmithKline Graduate Fellowship in Pharmacokinetics (to A.M.-H.).

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