Gestation Time-Dependent Pharmacokinetics of Intravenous (+)-Methamphetamine in Rats

Abstract

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 (t 1/2z ) of METH and (؉)-amphetamine (AMP; a pharmacologically active metabolite of METH) were not different on GD7, but by GD21, AMP t 1/2z was 37% longer than METH t 1/2z (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 t 1/2z was significantly shorter than metabolite AMP t 1/2z (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.

The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration

“…The semilogarithmic plasma concentration versus time profile obtained from intravenous bolus injection of PAL-353 at 5 mg/kg exhibited only one phase, indicating that a onecompartment model would fit the profile. Compared with previous research on the pharmacokinetics of two related compounds, amphetamine and methylphenidate, the elimination half-life and MRT for PAL-353 obtained in the current experiments were found to be similar to those reported for amphetamine (91 min and 95 min, respectively) in female Sprague Dawley rats in early pregnancy [28], but the elimination half-life for PAL-353 was 5.5 times the reported half-life reported for methylphenidate (24.6 min) [29]. Researchers utilized a subcutaneous osmotic mini-pump to provide continuous drug delivery while studying the chronic administration of amphetamine or related monoamine releasers for the treatment of CUD [30][31][32].…”

Meth math: modeling temperature responses to methamphetamine

“…Meth is rapidly absorbed from the peritoneum and then eliminated from the blood with a profile closely resembling a single-exponential process (23,76). Our data do not contain independent information about the volume of distribution.…”

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

“…METH and AMP brain and serum concentrations on GD21 were determined using a previously published method (White et al, 2011), with some modifications. Chromatographic separation and detection were achieved with a HILIC analytical column (Phenomenex) and an Acquity UPLC system connected to a Premier XE triple quadrupole mass spectrometer system (liquid chromatography coupled to tandem mass spectrometry; Waters, Milford, MA).…”

“…METH dose can cause maternal and fetal death (White et al, 2011). Although not directly toxic, a 1 mg/kg dose produces significant METH-induced behaviors in female rats (Milesi-Hallé et al, 2007).…”

“…The mAb4G9 dose was calculated as 0.56 mole-equivalent (assuming two binding sites per IgG) to the body burden of METH at 30 minutes. The body burden was determined by the following equation: body burden = dose  e 2lnt (Rowland and Tozer, 1995), where l n (the METH terminal elimination rate constant) was previously determined to be 0.0060/h in timed-pregnant rats on GD21 (White et al, 2011), and t was the 30-minute time point. 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.…”