title: Transplacental pharmacokinetics of diclofenac in perfused human placenta.
abstract: 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 TPT(ss) 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.
authors.affiliation: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Shintaku
authors.forename: Satoko
authors.initials: S
authors.lastname: Hori
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagata
authors.forename: Shoji
authors.initials: S
authors.lastname: Satoh
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Tsukimori
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nakano
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004008:Diclofenac / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D015233:Models, Statistical; D010539:Permeability / Q000187:drug effects; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D019344:Lactic Acid; D000983:Antipyrine