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Drug Metabolism and Disposition Fast Forward
First published on February 20, 2007; DOI: 10.1124/dmd.106.013029

0090-9556/07/3505-772-778$20.00
DMD 35:772-778, 2007

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Kinetic Analysis of the Transport of Salicylic Acid, a Nonsteroidal Anti-inflammatory Drug, across Human Placenta

Kyohei Shintaku, Yuka Arima, Yukihiko Dan, Tsutomu Takeda, Kentaro Kogushi, Masayuki Tsujimoto, Hideaki Nagata, Shoji Satoh, Kiyomi Tsukimori, Hitoo Nakano, Satoko Hori, Hisakazu Ohtani, and Yasufumi Sawada

Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences (K.S., Y.A., Y.D., T.T., K.K., M.T.), and Department of Reproduction and Gynecology, Graduate School of Medical Sciences (H.Nag., S.S., K.T., H.Nak.), Kyushu University, Fukuoka, Japan; and Department of Drug Informatics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (S.H., H.O., Y.S.)

The aim of this study was to develop a pharmacokinetic model to describe the transplacental transfer of drugs, based on the human placental perfusion study. The maternal and fetal sides of human placentas were perfused with salicylic acid together with antipyrine, a passive diffusion marker. The drug concentration in the placental tissue was determined at the end of perfusion. A compartment model consisting of maternal space, fetal intravascular space, and placental tissue was fitted to the observed concentration profiles of salicylic acid in the maternal and fetal effluents. The developed model could adequately explain the concentration profiles of salicylic acid in the effluents with influx clearances from maternal and fetal perfusates to placental tissue of 0.0407 and 0.0813 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates (k2 and k3) of 0.0238 and 0.176 min–1, respectively. The kinetics of antipyrine was adequately described by assuming rapid equilibrium between fetal perfusate and placental tissue compartments. The influx plasma clearance from the maternal side (K''1) in humans was estimated by taking into account the protein binding. The K''1/k2 value of salicylic acid was 1.07 ml/g cotyledon and was larger than that of antipyrine (0.642 ml/g cotyledon). We evaluated the transplacental transfer kinetics of salicylic acid by human placental perfusion study with various perfusion protocols. Based on the data obtained, we developed a pharmacokinetic model, which should enable us to estimate the influx profile of drugs into umbilical arterial blood from the maternal plasma concentration profile.

Address correspondence to: Yasufumi Sawada, Department of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sawada{at}mol.f.u-tokyo.ac.jp




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K. Shintaku, S. Hori, M. Tsujimoto, H. Nagata, S. Satoh, K. Tsukimori, H. Nakano, T. Fujii, Y. Taketani, H. Ohtani, et al.
Transplacental Pharmacokinetics of Diclofenac in Perfused Human Placenta
Drug Metab. Dispos., May 1, 2009; 37(5): 962 - 968.
[Abstract] [Full Text] [PDF]


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