Treatment with a monoclonal antibody against methamphetamine and amphetamine reduces maternal and fetal rat brain concentrations in late pregnancy.
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.
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
Sarah J
SJ
White
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
Howard P
HP
Hendrickson
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
William T
WT
Atchley
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
Elizabeth M
EM
Laurenzana
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
W Brooks
WB
Gentry
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
D Keith
DK
Williams
Department of Pharmacology and Toxicology, College of Medicine (S.J.W., W.T.A., E.M.L., W.B.G., S.M.O.), Department of Anesthesiology, College of Medicine (W.B.G.), Department of Pharmaceutical Sciences, College of Pharmacy (H.P.H.), and Department of Biostatistics, College of Public Health (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Pennsylvania State University, State College, Pennsylvania (E.M.L.).
S Michael
http://orcid.org/0000-0003-1403-2778
SM
Owens
D000661:Amphetamine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism*; D019540:Area Under Curve; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism; D006207:Half-Life; D008694:Methamphetamine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D011247:Pregnancy; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D008694:Methamphetamine; D000661:Amphetamine