THE ENANTIOSELECTIVE TERATOGENICITY OF 2-NORMAL-PROPYL-4-PENTYNOIC ACID (4-YN-VPA) IS DUE TO STEREOSELECTIVE INTRINSIC ACTIVITY AND NOT DIFFERENCES IN PHARMACOKINETICS

被引:20
作者
HAUCK, RS
ELMAZAR, MMA
PLUM, C
NAU, H
机构
[1] Institute of Toxicology and Embryopharmacology, Free University of Berlin
关键词
2-NORMAL-PROPYL-4-PENTYNOIC ACID; ENANTIOMERS; GAS CHROMATOGRAPHIC SEPARATION; PHARMACOKINETICS; STEREOSELECTIVE INTRINSIC ACTIVITY;
D O I
10.1016/0378-4274(92)90269-P
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
The present study was designed to investigate whether there are pharmacokinetic reasons for the enantioselective teratogenicity of R(+)-4-yn-VPA (low potency) and S(-)-4-yn-VPA (high potency). A gas chromatographic method was employed to determine 4-yn-VPA enantiomers in maternal plasma, brain, erythrocytes and in the embryo and decidua/extraembryonic membranes of the mouse following a single intraperitoneal dose of 300 mg/kg (+/-)-4-yn-VPA-Na on day 9 of gestation. Furthermore, the pharmacokinetics of R- and S-4-yn-VPA were studied in maternal plasma of day-8 pregnant mice following intraperitoneal administration of 300 and 500 mg (+/-)-4-yn-VPA-Na/kg body wt%., respectively. No significant difference in the pharmacokinetic profiles of the two enantiomers was detected in either the maternal organism or in the embryonic compartments. Thus, the two enantiomers reach the embryo in comparable concentrations during the sensitive period of organogenesis, but exhibit very different teratogenic activities. This study therefore indicates that the stereoselective teratogenicity of 4-yn-VPA is due to differences in intrinsic activities and not due to differences in the pharmacokinetics of the enantiomers.
引用
收藏
页码:145 / 153
页数:9
相关论文
共 14 条
[1]  
BJERKEDAL T, 1982, LANCET, V2, P1096
[2]   VALPROIC ACID PRENATAL EXPOSURE - ASSOCIATION WITH LIPOMYELOMENINGOCELE [J].
CARTER, BS ;
STEWART, JM .
CLINICAL PEDIATRICS, 1989, 28 (02) :81-85
[3]  
HAUCK R-S, 1990, Teratology, V41, P563
[6]   FETAL GROWTH, MAJOR MALFORMATIONS, AND MINOR ANOMALIES IN INFANTS BORN TO WOMEN RECEIVING VALPROIC ACID [J].
JAGERROMAN, E ;
DEICHL, A ;
JAKOB, S ;
HARTMANN, AM ;
KOCH, S ;
RATING, D ;
STELDINGER, R ;
NAU, H ;
HELGE, H .
JOURNAL OF PEDIATRICS, 1986, 108 (06) :997-1004
[7]   ENANTIOSELECTIVE ASPECTS OF DRUG-ACTION AND DISPOSITION - THERAPEUTIC PITFALLS [J].
JAMALI, F ;
MEHVAR, R ;
PASUTTO, FM .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1989, 78 (09) :695-715
[8]  
KAO J, 1981, Teratogenesis Carcinogenesis and Mutagenesis, V1, P367, DOI 10.1002/tcm.1770010405
[9]   A NEW MODEL FOR EMBRYOTOXICITY TESTING - TERATOGENICITY AND PHARMACOKINETICS OF VALPROIC ACID FOLLOWING CONSTANT-RATE ADMINISTRATION IN THE MOUSE USING HUMAN THERAPEUTIC DRUG AND METABOLITE CONCENTRATIONS [J].
NAU, H ;
ZIERER, R ;
SPIELMANN, H ;
NEUBERT, D ;
GANSAU, C .
LIFE SCIENCES, 1981, 29 (26) :2803-2813
[10]   WEAK ACIDS MAY ACT AS TERATOGENS BY ACCUMULATING IN THE BASIC MILIEU OF THE EARLY MAMMALIAN EMBRYO [J].
NAU, H ;
SCOTT, WJ .
NATURE, 1986, 323 (6085) :276-278