[Transplacental transport and feto-placental metabolism of drugs: study methods, therapeutic contributions 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 investigational field of clinical trials, only few studies exist concerning evaluation of the pregestational metabolism or transplacental transfer (TPT) of drugs. Questions are extensive and complex. Does TPT occur at a given gestational age (GA), in the context of a particular type of pathology, 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 characteristics)? 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 amniotic 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 authors review methods for the study of TPT developed both in vitro and in vivo. The current review covers the period between 1972 and 1993. Exchange mechanisms are complicated and models developed in vitro only partially reflect the actual equilibria which develop. These include: 1) the perfused cotyledon model, which while simple, elegant and inexpensive, offers only a localized and fixed view of pregnancy; 2) the necessary study, using microsomes, of placental metabolic capacity (enzyme cartography). In vivo study of TPT is based upon various multicompartmental pharmacokinetic models, some of which have been relatively validated in animals. The simplest indicator for the in vivo evaluation of TPT of a drug in the human species is determination of a feto-maternal blood concentrations ratio (usually performed at the time of separation). The usefulness and limitations of this parameter are controversial, and it would seem preferable to associate it with a kinetic profile of variations in blood concentrations established in the mother. Any extrapolation of a single result to fetal and adjacent tissues must be done with the greatest caution. Study of the TPT of therapeutically useful agents is essential to the understanding of their metabolism and is a prerequisite to the use of medications during pregnancy, bearing in mind that any such use must always be with the greatest care and with extremely well-founded indications.
Bourget
P
P
Service de Pharmacologie clinique, Hôpital Antoine Béclère, Clamart.
Roulot
C
C
Fernandez
H
H
D004992:Ethics, Medical; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008861:Microsomes / Q000378:metabolism; D008954:Models, Biological; D010599:Pharmacokinetics; D010920:Placenta / Q000098:blood supply / Q000378:metabolism; D011247:Pregnancy
Transfert transplacentaire et métabolisme foeto-placentaire des médicaments: méthodes d'étude, apports et implications thérapeutiques.