Significance of pharmacokinetic variables in reproductive and developmental toxicity. 1988

D Neubert
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, FR Germany.

1. As in other fields of toxicology, pharmacokinetic variables are of considerable significance for the assessment of reproductive or developmental toxicity. 2. When assessing the possibility of an adverse effect of a chemical on male or female fertility, in the majority of the cases no information on the concentration at the target is available. This may cause problems in the case of a 'negative' finding. 3. Prenatal toxicity takes place within a complex 'two-compartment' system (mother: conceptus); pharmacokinetic variables in both systems determine the concentration at the target (the conceptus). These variables may be expected to vary greatly during the different stages of development. While the contribution of maternal pharmacokinetics can easily be assessed, the pharmacokinetics within the embryo/foetus will remain largely unknown in man. 4. While it is quite feasible in animal experiments to study the transfer of a given chemical to the conceptus in vivo at various stages of pregnancy it is almost impossible to obtain such information for most developmental stages in man, except at the perinatal period (by sampling cord blood). For this reason during most risk assessments exposure of the embryo or fetus can only be roughly assumed from maternal plasma concentrations. 5. A significant capacity of foetal tissues (including liver) for metabolic transformation of many chemicals (e.g. via cytochrome-P-450-dependent monooxygenases) develops only perinatally in the usual rodent animal species. But in primates (including man) the activity of several such monooxygenases is substantial in liver already at early foetal stages. Much less information is available on the metabolic capacity for xenobiotics in extrahepatic tissues of primate embryos and foetuses. 6. Since pharmacokinetic variables (e.g. half-life) often differ considerably in laboratory rodents and in man a risk assessment for man on the basis of doses is often greatly misleading. It seems more justified to predict toxic effects on the basis of plasma levels. This aspect is of great significance and must be taken into consideration since the results of many routine studies are not suitable for risk assessments because pharmacokinetic variables were not considered when planning experimental studies. 7. Factors affecting the transfer of chemicals via mothers milk to the neonate are largely known today. But solid data on the pharmacokinetics of xenobiotics with respect to transfer to the milk and ensuing concentrations in the neonate are still lacking for the majority of relevant chemicals.(ABSTRACT TRUNCATED AT 400 WORDS)

UI MeSH Term Description Entries
D007231 Infant, Newborn An infant during the first 28 days after birth. Neonate,Newborns,Infants, Newborn,Neonates,Newborn,Newborn Infant,Newborn Infants
D008431 Maternal-Fetal Exchange Exchange of substances between the maternal blood and the fetal blood at the PLACENTA via PLACENTAL CIRCULATION. The placental barrier excludes microbial or viral transmission. Transplacental Exposure,Exchange, Maternal-Fetal,Exposure, Transplacental,Maternal Fetal Exchange
D008895 Milk, Human Milk that is produced by HUMAN MAMMARY GLANDS. Breast Milk,Human Milk,Milk, Breast
D010599 Pharmacokinetics Dynamic and kinetic mechanisms of exogenous chemical DRUG LIBERATION; ABSORPTION; BIOLOGICAL TRANSPORT; TISSUE DISTRIBUTION; BIOTRANSFORMATION; elimination; and DRUG TOXICITY as a function of dosage, and rate of METABOLISM. LADMER, ADME and ADMET are abbreviations for liberation, absorption, distribution, metabolism, elimination, and toxicology. ADME,ADME-Tox,ADMET,Absorption, Distribution, Metabolism, Elimination, and Toxicology,Absorption, Distribution, Metabolism, and Elimination,Drug Kinetics,Kinetics, Drug,LADMER,Liberation, Absorption, Distribution, Metabolism, Elimination, and Response
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D012098 Reproduction The total process by which organisms produce offspring. (Stedman, 25th ed) Human Reproductive Index,Human Reproductive Indexes,Reproductive Period,Human Reproductive Indices,Index, Human Reproductive,Indexes, Human Reproductive,Indices, Human Reproductive,Period, Reproductive,Periods, Reproductive,Reproductive Index, Human,Reproductive Indices, Human,Reproductive Periods
D004622 Embryo, Mammalian The entity of a developing mammal (MAMMALS), generally from the cleavage of a ZYGOTE to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the FETUS. Embryonic Structures, Mammalian,Mammalian Embryo,Mammalian Embryo Structures,Mammalian Embryonic Structures,Embryo Structure, Mammalian,Embryo Structures, Mammalian,Embryonic Structure, Mammalian,Embryos, Mammalian,Mammalian Embryo Structure,Mammalian Embryonic Structure,Mammalian Embryos,Structure, Mammalian Embryo,Structure, Mammalian Embryonic,Structures, Mammalian Embryo,Structures, Mammalian Embryonic
D005260 Female Females
D005314 Embryonic and Fetal Development Morphological and physiological development of EMBRYOS or FETUSES. Embryo and Fetal Development,Prenatal Programming,Programming, Prenatal
D005333 Fetus The unborn young of a viviparous mammal, in the postembryonic period, after the major structures have been outlined. In humans, the unborn young from the end of the eighth week after CONCEPTION until BIRTH, as distinguished from the earlier EMBRYO, MAMMALIAN. Fetal Structures,Fetal Tissue,Fetuses,Mummified Fetus,Retained Fetus,Fetal Structure,Fetal Tissues,Fetus, Mummified,Fetus, Retained,Structure, Fetal,Structures, Fetal,Tissue, Fetal,Tissues, Fetal

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