Treatment with a monoclonal antibody against methamphetamine and amphetamine reduces maternal and fetal rat brain concentrations in late pregnancy

Abstract

We hypothesized that treatment of pregnant rat dams with a dual reactive monoclonal antibody (mAb4G9) against (+)-methamphetamine [METH; equilibrium dissociation rate constant (KD) = 16 nM] and (+)-amphetamine (AMP; KD = 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.

Fig. 1.

Average METH (A and C) and AMP (B and D) concentration-versus-time profiles in maternal and fetal sera (A and B) and brains (C and D) on GD21 in control animals used for calculating baseline pharmacokinetic values (Tables 1 and 2). These animals did not receive antibody. The dams received 1 mg/kg i.v. METH followed 30 minutes later with vehicle (buffer, as indicated by the arrows on the serum graphs). Blood samples up to the 30-minute time point were collected from a venous cannula. Remaining samples were collected after sacrificing the dams. The solid lines represent either a WinNonlin best-fit line to the maternal serum METH (A) and AMP (B) concentration-time data, or a linear regression best-fit line to the terminal log concentration-time data (all other plots). All values are represented by mean ± S.D.; n = 4 per time point. *, Indicates a significant difference (P < 0.05) from corresponding maternal serum or brain concentrations.

Fig. 2.

Average maternal (A and B) and fetal (C and D) serum concentration-versus-time profiles of METH (A and C) and AMP (B and D) in dams administered 1 mg/kg METH followed at 30 minutes by vehicle or 0.56 mole-equivalent of mAb4G9 treatment. The studies were conducted on GD21. The solid lines represent a linear regression best-fit line to the terminal log concentration-versus-time data. A best-fit line to the terminal phase was not performed on animals with mAb4G9 treatment, because previous studies suggest the terminal elimination phase (t_1/2 ∼7 days) would be substantially longer than the current 5-hour study. The arrows (on the serum graphs) indicate the time of vehicle or mAb4G9 administration. All values are represented by mean ± S.D. (n = 4/time point). *, Indicates a significant difference from controls (P < 0.05).

Fig. 3.

Average percentage of METH (A and C) and AMP (B and D) protein binding in the maternal serum (A and B) and fetal serum (C and D) over time after maternal administration of a 1 mg/kg i.v. METH dose on GD21. Thirty minutes after the pregnant rats received i.v. METH, mAb4G9 or vehicle was administered. All values are represented by mean ± S.D. (n = 4/time point). *, Indicates a significant difference compared with control values. †, Indicates a significant difference compared with maternal control dams. ‡, Indicates a significant difference compared with mAb-treated maternal values (P < 0.05 in all cases).

Fig. 4.

Average METH (A and C) and AMP (B and D) concentration-versus-time profiles of maternal (A and B) and fetal (C and D) brains after maternal administration of i.v. METH followed 30 minutes later by vehicle or mAb4G9. The solid lines represent the linear regression fit to the terminal log concentration-versus-time data. All values are represented by mean ± S.D. (n = 4/time point). *, Indicates a significant difference compared with controls. †, Indicates a significant difference compared with vehicle-treated maternal values. ‡, Indicates a significant difference compared with mAb-treated maternal values (P < 0.05 in all cases).