TRANSPLACENTAL PASSAGE AND FETOPLACENTAL METABOLISM OF DRUGS - STUDY DESIGN, THERAPEUTIC CONTRIBUTION AND IMPLICATIONS

Pregnancy is a specific dynamic state and the potential usefulness of caring for a fetal and/or adjacent disorder by treating the mother is now well established. Pregnant women being excluded from the investiga tional field of clinical trials, only few studies exist concerning eva luation of the pergestational metabolism or transplacental transfer (T PT) of drugs. Questions are extensive and complex. Does TPT occur at a given gestational age (GA), in the context of a particular type of pa thology, when a drug is administered by a certain dosage regimen ? If this is the case, what is the rapidity of penetration of the products of conception by the drug (bearing in mind its physical-chemical chara cteristics) ? Need harmful adverse effects on the child be feared ? Is such penetration desirable, of no consequence or dangerous ? Does the possibility exist of accumulation in the placenta, fetal tissue or am niotic fluid ? Should such findings modify the therapeutic regimens of drugs given to expectant mothers ? After dealing with the ethical and physiological context in which such research is undertaken, the autho rs review methods for the study of TPT developed both in vitro and in vivo. The current review covers the period between 1972 and 1993. Exch ange mechanisms are complicated and models developed in vitro only par tially reflect the actual equilibria which develop. These include : 1) the perfused cotyledon model, which while simple, elegant and inexpen sive, offers only a localized and fixed view of pregnancy; 2) the nece ssary study, using microsomes, of placental metabolic capacity (enzyme cartography). In vivo study of TPT is based upon various multicompart mental pharmacokinetic models, some of which have been relatively vali dated in animals. The simplest indicator for the in vivo evaluation of TPT of a drug in the human species is determination of a fete-materna l blood concentrations ratio (usually performed at the time of separat ion). The usefulness and limitations of this parameter are controversi al, and it would seem preferable to associate it with a kinetic profil e of variations in blood concentrations established in the mother. Any extrapolation of a single result to fetal and adjacent tissues must b e done with the greatest caution. Study of the TPT of therapeutically useful agents is essential to the understanding of their metabolism an d is a prerequisite to the use of medications during pregnancy, bearin g in mind that any such use must always be with the greatest care and with extremely well-founded indications.