https://stacks.cdc.gov/view/cdc/37676/cdc_37676_DS1.pdf

Toxicological Profile for Lead

Before marketing a new drug, the manufacturer almost never tests the product in pregnant women to determine its effects on the fetus. Consequently, most drugs are not labeled for use during pregnancy. Typically, descriptions of drugs that appear in the Physicians' Desk Reference and similar sources contain statements such as, “Use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus.” Since the risk has been adequately established for only a few drugs, physicians caring for pregnant women have very little information to help them decide whether the potential benefits to the mother outweigh . . .

Drugs in Pregnancy

Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

Enterohepatic circulation: physiological, pharmacokinetic and clinical implications.

γ-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABAAand GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB. The physiological, pharmacological, and molecular characteristics of GABAA receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.

GABA and GABA receptors in the central nervous system and other organs.

In addition to its role as an inhibitory neurotransmitter, γ-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 −/− mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 −/− mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 −/− mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.

https://www.pnas.org/content/pnas/94/12/6496.full.pdf

Cleft palate and decreased brain gamma -aminobutyric acid in mice lacking the 67-kda isoform of glutamic acid decarboxylase

Diphenylhydantoin was teratogenic and caused prenatal death in Swiss-Webster mice. Most deaths resulted after single treatment on days 10, 11, 12, 14, and 15. Fetal body weight was significantly reduced in a dose-related manner after single treatment on days 9 to 15. Single injections of diphenylhydantoin produced open eye, ectrodactyly, cleft lip, cleft palate, hydronephrosis, and internal hydrocephalus. Skeletal defects noted were incomplete ossification of sternebrae or cervical centra, unfused sternebrae, and fused vertebrae. Long bones were shortened in a day- and dosage-dependent fashion. Mortality, teratogenesis, and effect on fetal growth were day- and dosage-dependent as was the spectrum of anomalies produced.

Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice

Teratogenicity, fetal toxicity, and placental transfer of lead nitrate in rats

Diphenylhydantoin teratogenicity in rats.

SummaryDiphenylhydantoin, 50 mg/kg, s.c., was administered to primigravid Swiss-Webster and A/J mice during early (days 7, 8, 9) and late (days 11, 12, 13) embryogenesis. Litters were delivered by caesarean section on day 18 of gestation, weighed, examined, and measured. Resorption rates were not altered in either strain treated during early embryogenesis. The A/J, but not Swiss-Webster, mice treated during late embryogenesis had a significant (p<0.05) increase in resorption. Diphenylhydantoin resulted in reduced fetal weight in both strains when given during late embryogenesis. Fetal long bone length, measured in alizarin red stained fetuses, was shortened only in late treated Swiss-Webster mice. The incidence of cleft palate was significantly elevated in late, but not early, treated progeny of both strains. Cleft palate with cleft lip occurred only in A/J mice; the rate was not different from vehicle treated controls. No other soft tissue malformations were found in either strain following Bouin's fixat...

Bernard A. Becker

Papers

Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice

Teratogenicity, fetal toxicity, and placental transfer of lead nitrate in rats

Diphenylhydantoin teratogenicity in rats.

Teratogenic Effects of Diphenylhydantoin in Swiss-Webster and A/J Mice

Teratogenicity of oral diazepam and diphenylhydantoin in mice.