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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)248-256
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Volume73
Issue number2
DOIs
Publication statusPublished - 2012 Feb
Externally publishedYes

Fingerprint

Ductus Arteriosus
Anti-Inflammatory Agents
Perfusion
Antipyrine
Pharmacokinetics
Salicylic Acid
Diclofenac
Pharmaceutical Preparations
Oral Administration
Mothers
Constriction
Persistent Fetal Circulation Syndrome
Drug-Related Side Effects and Adverse Reactions
Pulmonary Artery
Pregnant Women

Keywords

  • Constriction of ductus arteriosus
  • Fetal toxicity
  • Human placental perfusion study
  • Nonsteroidal anti-inflammatory drug

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies. / Shintaku, Kyohei; Hori, Satoko; Satoh, Hiroki; Tsukimori, Kiyomi; Nakano, Hitoo; Fujii, Tomoyuki; Taketani, Yuji; Ohtani, Hisakazu; Sawada, Yasufumi.

In: British Journal of Clinical Pharmacology, Vol. 73, No. 2, 02.2012, p. 248-256.

Research output: Contribution to journalArticle

Shintaku, Kyohei ; Hori, Satoko ; Satoh, Hiroki ; Tsukimori, Kiyomi ; Nakano, Hitoo ; Fujii, Tomoyuki ; Taketani, Yuji ; Ohtani, Hisakazu ; Sawada, Yasufumi. / Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies. In: British Journal of Clinical Pharmacology. 2012 ; Vol. 73, No. 2. pp. 248-256.
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AU - Tsukimori, Kiyomi

AU - Nakano, Hitoo

AU - Fujii, Tomoyuki

AU - Taketani, Yuji

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AU - Sawada, Yasufumi

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AB - 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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