Fetal drug metabolism and its possible clinical implications.

The ability of the human conceptus to metabolise xenobiotics during early gestation is now well established. Specific activities of liver enzymes have been demonstrated to exist in the late embryonic phase for numerous cytochrome P450 monooxygenases and many phase II enzymes such as glutathione-, N-acetyl-, sulpho- and uridine diphosphate-glucuronosyltransferase. As in the adult, fetal drug metabolism may function in a dual manner, either as a protective mechanism against chemical aggression when transforming active molecules into inactive ones, or as a toxifying system when transforming innocuous compounds into reactive metabolites. Recent advances in the understanding of enzyme variabilities at molecular and functional levels illustrate the necessity of studying these variations in the human fetus as well as in adults, since the combination of genetic, developmental and environmental factors seem to control fetal enzyme activities and ultimately determine the variability in individual susceptibility to chemicals in utero. Despite the scarcity of well documented cases of adverse fetal reactions resulting directly from metabolic toxicity, the clinical relevance of the potential role of biotransformation in generating fetal toxicity is a strong appeal to promote further studies dealing with the ontogeny of drug-metabolising capacity and its regulation.

Serum protein binding of diazepam and propranolol in the feto-maternal unit from early to late pregnancy.

Paired samples of maternal and fetal serum were obtained in 65 pregnancies between 13 and 41 weeks gestation. Concentrations of albumin, alpha 1-acid glycoprotein (alpha 1-AGP) and free fatty acids (FFA) were estimated in all samples and the in-vitro binding of diazepam and propranolol was estimated. The free fraction of diazepam in fetal serum was very high in early gestation and decreased with advancing gestation to reach maternal values around the 30th week. After 35 weeks gestation, values were generally lower in fetal than in maternal serum. Fetal serum binding of diazepam correlated with fetal albumin levels and gestational age. The ratio of the fetal/maternal free diazepam fraction correlated negatively with the fetal/maternal serum albumin concentration ratio. The maternal/fetal free diazepam fraction ratio correlated positively with gestational age. The free fraction of propranolol in fetal serum was higher than in maternal serum in early pregnancy and decreased with advancing gestation but always remained higher than the maternal values. The fetal/maternal free propranolol fraction ratio was negatively correlated with the fetal/maternal alpha 1-AGP serum concentration ratio. The maternal/fetal free propranolol fraction ratio was positively correlated with gestational age. Serum protein binding of propranolol was correlated with serum albumin concentrations in fetal samples but not in maternal samples. Serum FFA concentrations were not correlated with serum protein binding except for maternal serum binding of diazepam. For toxicological reasons it is advisable to monitor maternal blood for free concentrations of drugs that exhibit concentration-dependent protein binding or which can be displaced from binding sites by other drugs or endogenous compounds such as FFA.

Serum protein binding of valproic acid in fetus-mother pairs throughout pregnancy: correlation with oxytocin administration and albumin and free fatty acid concentrations.

The protein binding (expressed as percent free drug fraction) of the antiepileptic drug valproic acid (VPA) was studied in 65 fetus-mother pairs from weeks 13 to week 41 of gestation. The fetal free fractions (expressed as percent of total concentrations) of VPA were exceedingly high (greater than 50%) during weeks 13 to 16 of gestation; these values decreased to 20% by week 20 and further decreased gradually to 10% at term. There was a highly significant negative correlation between free VPA fractions and fetal albumin concentrations. Maternal free fractions of VPA gradually increased from 10% during early pregnancy to 20% at term. The free fractions of VPA were significantly higher in mothers who had received oxytocin. Thus, protein binding in the fetus exceeded that of the mother at term, whereas the converse was true during early gestation. These results agree with previous in vivo findings. It is likely that the free concentrations in the mother determine the drug effects and toxicity in both the mother and the fetus. Intermittent drug administration--particularly of large single doses--could result in a transient increase of the free concentrations of VPA, particularly because of the strong concentration dependence of VPA protein binding. Increased free fractions can also be expected from increased concentrations of displacing agents of endogenous or exogenous origin (other drugs).

Changes in serum albumin and alpha 1-acid glycoprotein concentrations during pregnancy: an analysis of fetal-maternal pairs.

The concentration of the two principal drug-binding proteins, albumin and alpha 1-acid glycoprotein, were measured in 44 paired fetal and maternal serum samples obtained at between 12 and 41 weeks gestation. Maternal serum albumin concentrations ranged between 25 and 35 g/l during this period. Fetal serum albumin was much lower in early gestation, ranging from 7.5 to 16 g/l at 12-15 weeks. With advancing age there was a linear increase so that at 30 weeks the fetal and the maternal serum albumin concentrations were in the same range and after 35 weeks the fetal concentrations exceeded the maternal by some 20%. Thus, the mean fetal/maternal serum concentration ratio of albumin increases from early pregnancy to term: 0.38 at 12-15 weeks; 0.66 at 16-25 weeks; 0.97 at 26-35 weeks; and 1.2 at greater than 35 weeks gestation. Maternal serum alpha 1-acid glycoprotein concentrations were scattered widely between 0.38 and 1.05 g/l. With the technique used fetal serum concentrations were hardly detectable before 16 weeks. Thereafter they increased at a constant rate, but never attained the maternal values. Near term a fetal/maternal serum concentration ratio of 0.37 was reached. These changes in protein concentrations may have important pharmacological implications.

Drug kinetics in pregnancy.

Any drug given to a pregnant woman must be considered as possibly harmful in the fetus, since all drugs administered to the mother cross the placental membrane, although at different rates. Important physiological changes occur in pregnancy, which may influence the kinetics of drugs. Differences in gastrointestinal function are likely to alter drug absorption rates in the stomach or gut. Ventilatory alterations modify pulmonary drug absorption or elimination. Important changes in haemodynamics and alterations in body water compartments influence drug distribution and elimination. Renal drug elimination is generally enhanced, whereas hepatic drug elimination may be modified in different ways. Computerised pharmacokinetic models representing the compartmental aspects of the fetal-maternal unit and fetal-maternal drug interrelationships may be used to predict kinetic consequences of fetal drug exposure. Such information may be a useful guide for the clinical use of drugs during pregnancy, particularly for treatment of fetal disease.

Maternal and neonatal elimination of amobarbital after treatment of the mother with barbiturates during late pregnancy.

Plasma half-lives of amobarbital were determined in newborn children of 10 mothers who had been treated with barbiturates for hypertension in pregnancy for 6 to 42 days prior to delivery. Five mothers had received amobarbital, 200 mg daily, and 5, phenobarbital, 60 to 180 mg daily. Half-lives in 7 of the babies ranged from 16.6 to 49.4 hr, comparable to those previously reported in babies of mothers who had received only a single dose of amobarbital. Thus there was no evidence of induction of amobarbital hydroxylation in these children. Two babies who had a greater than normal rise in serum bilirubin had longer half-lives (86.1 and 117.7 hr). In 1 baby whose mother had membranous glomerulonephritis, plasma amobarbital concentration did not significantly change over the period of the study.