Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretics and analgesics in the field of gynaecology. When given to women during full-term pregnancy, diclofenac, an NSAID, readily permeates into fetal blood, inhibits the synthesis of prostaglandins and constricts the ductus arteriosus (DA), and may cause pulmonary hypertension and/or transient right-sided hypertrophic cardiomyopathy in the newborn [1, 2]. Salicylic acid leads to pulmonary hypertension in the newborn in a similar manner . However, the differences in fetal toxicity among NSAIDs remain to be fully investigated. Therefore, the ability to predict fetal toxicity of NSAIDs quantitatively at full-term pregnancy would be of clinical value.
Fetal toxicity is considered to be determined by both the maternal-to-fetal transfer of drugs (pharmacokinetics; PK) and the intrinsic toxicity (pharmacodynamics; PD). While the latter, such as constriction of fetal DA, can be evaluated in rats [4, 5], prediction of PK is difficult, because maternal-to-fetal transfer of drugs is regulated by the placenta. Animal studies may not be helpful to predict human fetal PK because of interspecies differences in the structural and functional features of the placenta. We have developed a method to evaluate quantitatively transplacental pharmacokinetic (TP-PK) parameters between maternal or fetal blood and placenta by applying a novel PK model [6, 7] to the results of human placental perfusion study . This method allows us to estimate the concentration profile of a drug in fetal blood from the maternal plasma profile.
The aim of this study was to predict quantitatively the fetal toxicity (constriction of the fetal DA) after maternal administration of NSAIDs by means of a PK/PD approach using TP-PK parameters estimated from our human placental perfusion study, pharmacokinetic data in humans and fetal toxicity estimated in rats.