TY - JOUR T1 - Transplacental Pharmacokinetics of Diclofenac in Perfused Human Placenta JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 962 LP - 968 DO - 10.1124/dmd.108.024349 VL - 37 IS - 5 AU - Kyohei Shintaku AU - Satoko Hori AU - Masayuki Tsujimoto AU - Hideaki Nagata AU - Shoji Satoh AU - Kiyomi Tsukimori AU - Hitoo Nakano AU - Tomoyuki Fujii AU - Yuji Taketani AU - Hisakazu Ohtani AU - Yasufumi Sawada Y1 - 2009/05/01 UR - http://dmd.aspetjournals.org/content/37/5/962.abstract N2 - The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of l-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with l-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPTss value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of l-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min–1, respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with l-lactic acid. The American Society for Pharmacology and Experimental Therapeutics ER -