In vitro models to predict the in vivo mechanism, rate and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus

摘要: Abstract Objective: We tested the hypothesis that mechanism, rate, and extent of in vivo placental transfer dideoxynucleoside drugs against human immunodeficiency virus can be predicted by vitro perfused placenta drug octanol-water partition coefficient. Study Design: Near-term pregnant macaques ( Macaca nemestrina ) underwent long-term catheterization for administration 4 dideoxynucleosides virus: zidovudine, didanosine, zalcitabine, stavudine. Maternal plasma, fetal amniotic fluid concentrations were determined frequently after intravenous bolus and/or infusion administered into maternal or circulation on separate occasions. Antipyrine was included all experiments as a marker blood flow. The compared with findings obtained others. Results: mechanism rate antipyrine-normalized highly correlated those observed vivo. (fetal/maternal steady-state plasma concentration ratio) also both clearance (clearance index) model r 2 = 0.95, clearance-index model) coefficient 0.99, partition-coefficient model). To determine predictive capacity these correlative models, we fetal/maternal ratio each excluding data from fit. Both models to predict resulted good predictions (mean error: model=−1.2%; model=3.9%). Conclusions: propose our will accurately virus. may applicable other classes drugs, regardless therapeutic category, provided passively diffuse across placenta. Such result expedite phase 1 clinical trials women. (Am J Obstet Gynecol 1999;180:198−206.)