Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies

• Published in: British journal of clinical pharmacology 2012-02, Vol.73 (2), p.248-256
• Main Authors: Shintaku, Kyohei, Hori, Satoko, Satoh, Hiroki, Tsukimori, Kiyomi, Nakano, Hitoo, Fujii, Tomoyuki, Taketani, Yuji, Ohtani, Hisakazu, Sawada, Yasufumi
• Format: Article
• Language: English
• Subjects: Abnormalities, Drug-Induced - etiology; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Antipyrine - pharmacokinetics; Antipyrine - toxicity; Biological and medical sciences; Cardiology. Vascular system; Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava; constriction of ductus arteriosus; Diclofenac - pharmacokinetics; Diclofenac - toxicity; Dose-Response Relationship, Drug; Female; Fetal Development - drug effects; fetal toxicity; Fetus - drug effects; Heart; human placental perfusion study; Humans; Maternal-Fetal Exchange - drug effects; Medical sciences; Models, Biological; nonsteroidal anti‐inflammatory drug; Perfusion; Pharmacokinetic Dynamic Relationships; Pharmacology. Drug treatments; Placenta - drug effects; Placenta - metabolism; Pregnancy; Pregnancy Complications, Cardiovascular - chemically induced; Rats; Salicylic Acid - pharmacokinetics; Salicylic Acid - toxicity
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2011.03921.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) in full‐term pregnant women leads to fetal or neonatal toxicity. 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. WHAT THIS STUDY ADDS • This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. • This study shows that the fetal risk of diclofenac is higher than that of salicylic acid and antipyrine using the novel method. • Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs. AIM The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) in full‐term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies. METHODS Human fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration–response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats. RESULTS The risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine. CONCLUSIONS This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting hum