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

Authors

  • Kyohei Shintaku,

    1. Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
    2. Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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  • Satoko Hori,

    1. Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
    2. Interfaculty Initiative in Information Studies, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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  • Hiroki Satoh,

    1. Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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  • Kiyomi Tsukimori,

    1. Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan and
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  • Hitoo Nakano,

    1. Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan and
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  • Tomoyuki Fujii,

    1. Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
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  • Yuji Taketani,

    1. Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
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  • Hisakazu Ohtani,

    1. Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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  • Yasufumi Sawada

    Corresponding author
    1. Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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Dr Yasufumi Sawada, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81 3 5841 2271, Fax: +81 3 5841 1097. E-mail: sawada@mol.f.u-tokyo.ac.jp

Abstract

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 human fetal toxicity of drugs.

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