Placental drug transfer: effects of gestational age and species

The available evidence suggests that for most drugs, adverse effects in the fetus may vary with gestational state and among species due to: (i) changes in the fetal exposure to the drug (i.e. due to changes in the pharmacokinetics of the drug in the mother and/or the fetus), or to (ii) changes in the susceptibility of the fetus to the drug. The fetal exposure to a drug during gestation is influenced more by the varying capacity of mother and/or fetus to eliminate the drug than by any intrinsic 'barrier' phenomenon at the placenta. Although differential maternal/fetal protein binding, active transplacental transport processes and 'ion-trapping' effects may influence the fetal exposure of some drugs, the main mechanisms by which fetal exposure may be modulated during pregnancy are via the capacity for irreversible drug elimination--by the fetus or, less often, by the placenta. The susceptibility of a fetus to adverse drug reactions is determined by the ontogeny of vital processes and the nature of the interaction between the drug and the process. Hence 'gestational state' and 'species' dependent differences in adverse drug effects, in the presence of a constant level of exposure of drug, reflect the time dependent appearance of these processes and the differences in ontogeny of the processes among species. At present, no studies have attempted to relate the measured fetal drug exposure to the intensity of a drug response at different stages of gestation or among species. Although there is a dearth of information in this field, it is apparent that in all species the placentas of all species pose little obstruction to the passage of xenobiotics (including drugs), to the fetus. The consequence of this exposure will depend on a myriad of pharmacokinetic and pharmacodynamic considerations for a given substance in a given species. Hence the outcome cannot be predicted, but must be empirically determined. Extrapolation of findings among different drugs, species and gestational states must be undertaken with caution, recognizing the above considerations and limitations.