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

Kyohei Shintaku, Satoko Hori, Hiroki Satoh, Kiyomi Tsukimori, Hitoo Nakano, Tomoyuki Fujii, Yuji Taketani, Hisakazu Ohtani, Yasufumi Sawada

研究成果: Article査読

11 被引用数 (Scopus)

抄録

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 human fetal toxicity of drugs.

本文言語English
ページ(範囲)248-256
ページ数9
ジャーナルBritish journal of clinical pharmacology
73
2
DOI
出版ステータスPublished - 2012 2
外部発表はい

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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