Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies.
OBJECTIVE
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.
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Kyohei
K
Shintaku
Satoko
S
Hori
Hiroki
H
Satoh
Kiyomi
K
Tsukimori
Hitoo
H
Nakano
Tomoyuki
T
Fujii
Yuji
Y
Taketani
Hisakazu
H
Ohtani
Yasufumi
Y
Sawada
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000633:toxicity*; D000983:Antipyrine / Q000493:pharmacokinetics / Q000633:toxicity; D004008:Diclofenac / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005333:Fetus / Q000187:drug effects*; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D008954:Models, Biological; D010477:Perfusion; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced; D051381:Rats; D020156:Salicylic Acid / Q000493:pharmacokinetics / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D020156:Salicylic Acid; D000983:Antipyrine
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