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1.  The Metabolism and Transplacental Transfer of Oseltamivir in the Ex Vivo Human Model 
Oseltamivir phosphate is extensively metabolized in the ex vivo human placenta model, and the transplacental passage of the metabolite oseltamivir carboxylate is incomplete. Objective. To evaluate the metabolism and transplacental transfer of oseltamivir (Tamiflu) in the ex vivo human placental model. Study Design. Perfusion studies were performed in six placentas from term, uncomplicated deliveries. Concentrations of oseltamivir phosphate (OP) that were 5-6 fold, 20–30 fold, and 600–800 fold above the therapeutic peak were tested, as neither OP nor its active metabolite, oseltamivir carboxylate (OC), could be detected at near-therapeutic concentrations. The transplacental transfer and accumulation of OC were assessed using the 14C antipyrine reference method. Results. OP was extensively metabolized to OC. In the 4 placentas with the highest concentration of OP, OC had a mean clearance index of 0.13 ± 0.08, suggesting that transplacental passage occurs at a relatively low rate. Measurable fetal accumulation occurred in the two placentas with the highest initial concentrations. Conclusions. Oseltamivir phosphate was extensively metabolized in the ex vivo model. Transplacental transfer of the metabolite was incomplete and accumulation was minimal.
PMCID: PMC2413047  PMID: 18551180
2.  The Bidirectional Transfer and Fetal Vascular Pressure Changes Due to the Presence of 125 I-Labeled Inhibin A in the ex-vivo Human Placental Model 
Objective: The purpose of this study was to investigate the transport of inhibin A and to determine its effects on fetal vascular pressure at elevated levels in the human placenta using 125I -labeled synthetic glycoprotein.
Methods: Synthetic inhibinAwas prepared and was shown to be consistent with the natural form by high-pressure liquid chromatography (HPLC) and molecular weight determination by gas-chromatography mass spectrometry. The standardized Na125I process yielded 125I -labeled inhibin A with a radioactivity of 106 cpm/μg. This compound was placed in the human placenta in maternal–fetal and fetal–maternal studies using antipyrine and 14C -labeled inulin as controls to determine the bidirectional transfer of the compound.
Results: Maternal–fetal and fetal–maternal clearance indices were 0.045± 0.003 and 0, respectively. In eight placentas there was no evidence of vascular pressure changes due to the presence of up to 5000 pg of inhibin A.
Conclusions: There is minimal maternal–fetal transfer and no detectable fetal–maternal transfer in normotensive and pregnancy-induced hypertensive placentas. In addition, there are no pressure changes in the fetal vascular system due to the clinically significant levels of inhibin A.
PMCID: PMC1852274  PMID: 14627215
3.  Ex Vivo Human Placental Transfer of Anti-Human Immunodeficiency Virus Compounds 
Objective: The transfer of anti-human immunodeficiency virus (HIV) drugs has been studied in the ex vivo human placental model. There is a paucity of information on the placental transfer of these drugs because of ethical considerations and the expense involved in the use of the non-human primate model.
Methods: The standardized ex vivo human placental model was used in these studies and the clearance index in relationship to antipyrine was used to determine the role of transfer of non-nucleosides, nucleosides, and a protease inhibitor. Several of the nucleosides and ritonavir were combined with zidovudine (AZT) to determine the effect of the combinations.
Results: All non-nucleosides, nucleosides, and the protease inhibitor were found to cross the human placenta by simple diffusion, although at variable rates. Ritonavir did not diffuse as rapidly as the nucleosides, but some diffusion was noted at peak concentrations.
Conclusions: Ex vivo perfusion studies agree with those determined in the non-human primate model and with data from existing clinical trials.
PMCID: PMC2364554  PMID: 18476157
4.  Ex Vivo Human Placental Transfer of Rifampin and Rifabutin 
Objective: The purpose of this study was to determine the ex vivo human placental transfer of rifampin and rifabutin.
Methods: Seven placentas from uncomplicated term vaginal or cesarean deliveries were studied utilizing the ex vivo single cotyledon perfusion system. Antipyrine was used for the reference compound in the determination of the clearance indices of rifampin and rifabutin.
Results: The clearance indices of rifampin at maternal concentrations of 1.0 and 10.0 μg/ml were 0.12 ± 0.05 and 0.12 ± 0.11, respectively. The clearance indices of rifabutin at maternal concentrations of 1.0 and 10.0 μg/ml were 0.44 ± 0.11 and 0.37 ± 0.15, respectively.
Conclusions: Because of its greater lipophilicity, rifabutin was found to have a greater clearance than rifampin. However, because of rifabutin's trend toward greater deposition in tissue, there was proportionately less accumulation of rifabutin in the fetal circulation when compared to rifampin.
PMCID: PMC2364518  PMID: 18476118
5.  Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague-Dawley Rats 
Objective: The purpose of the present investigation was to analyze the effets of zidovudine on the postimplantation embryo and fetus.
Methods: Pregnant Sprague-Dawley rats were given various doses (10 mg/kg, 30 mg/kg, 150 mg/kg) of zidovudine or saline by an endotracheal tube during the period of embryogenesis (days 6–8, 9–11, 6–11 postconception). The animals were sacrificed on days 18–19 of pregnancy, and their fetuses were removed by hysterotomy. Autopsies under low (15×) and high (40×) power light microscopy were performed on all fetuses.
Results: There was no statistically significant difference among the groups with respect to maternal weight gain. There were more pregnancy resorptions in the group receiving high-dose zidovudine (150 mg/kg/day) throughout embryogenesis than in the control group (P = 0.001, respectively). Four major structural anomalies were noted among the 689 fetuses examined, but zidovudine was not associated with an increased frequency of congenital anomalies in rats when it was administered in doses similar to, 3-, and 15-fold higher than the regimen recommended for adult humans. The drug, however, was embryocidal in the high-dose group (P = 0.002).
Conclusions: These findings are consistent with previous studies of preimplantation mouse embryos that demonstrated an embryocidal effect on preimplantation conceptuses. In summary, post-implantation embryonic zidovudine exposure was associated with significantly increased pregnancy losses (resorptions and intrauterine deaths).
PMCID: PMC2364389  PMID: 18475397

Results 1-5 (5)