The metabolism and transplacental transfer of oseltamivir in the ex vivo human model.

UNLABELLED: 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 (14)C 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.

Placental transfer of rosiglitazone in the ex vivo human perfusion model.

OBJECTIVE: The objective of the study was to determine transplacental passage of rosiglitazone (Avandia) using the ex vivo human placental model. STUDY DESIGN: Perfusion studies were performed on 10 placentas from term, uncomplicated deliveries. Concentrations typical for an 8-mg oral dose (216 to 692 ng/mL) as well as 2- to 3-fold increased concentrations were tested (734 to 1261 ng/mL). Transfer of rosiglitazone was assessed and accumulation was determined using the 14C-antipyrine reference method. RESULTS: The clearance index for low and high concentrations were 0.14 +/- 0.04 and 0.20 +/- 0.08, suggesting that the drug passes through the placenta at a relatively low rate. Fetal accumulation occurred in only 1 of 5 placentas at 16.4 ng/mL (5%) for the 8-mg dose and in 2 of 5 placentas ranging from 0 to 74 ng/mL (5% to 8%) at higher concentrations. CONCLUSION: There is minimal transfer and fetal accumulation of rosiglitazone according to the ex vivo human perfusion model.

Transfer of meropenem in the ex vivo human placenta perfusion model.

OBJECTIVES: To determine maternal-fetal transplacental passage of meropenem in the ex vivo human perfusion model. STUDY DESIGN: Term placentae (n = 6) were collected immediately after delivery. A single cotyledon was localized, perfused and stabilized with physiologic Eagles minimal essential medium containing 3% bovine albumin and heparin as described by Chalier (Chalier JC. Criteria for evaluating perfusion experiments and presentation results. Contrib Gynecol Obstet 1985; 13:32 - 39). Meropenem was added to the maternal medium in concentrations similar to maternal serum peak and trough levels, then perfused through the maternal circulation of the cotyledon. To assess transfer and accumulation, fluid aliquots from both the maternal and fetal compartments were collected over an hour at defined intervals in an open and closed system. Antipyrine 14C was added to the medium in order to calculate the transport fraction and clearance indexes. Meropenem and antipyrine 14C concentrations were determined by High-pressure Liquid Chromatography and liquid scintillation, respectively. RESULTS: Mean antipyrine transport fraction was 2.33 + 0.25. Maternal and fetal mean meropenem peak concentrations were 54.3 + 3.3 microg/ml and 2.2 + 0.18 microg/ml, respectively. Whereas, maternal and fetal mean trough concentrations were 12.7 + 1.3 microg/ml and 0.41 + 0.10 microg/ml, respectively. Mean peak clearance index was 0.077 + 0.007 and the mean trough was 0.052 + 0.015. Mean accumulation for the peak and trough concentrations of meropenem were 0.9 and 2.95 microg/ml, respectively. CONCLUSIONS: Transplacental passage of meropenem was incomplete in the ex vivo human placental perfusion model. Accumulation was also noted in the fetal compartment.

Transfer of inflammatory cytokines across the placenta.

OBJECTIVE: The purpose of this study was to determine whether the placental transfer of interleukin (IL)-1alpha, IL-6, and tumor necrosis factor-alpha (TNF-alpha) occurs. METHODS: Four normal-term placentas were perfused for maternal-fetal transfer of the cytokines, 2 placentas for fetal-maternal transfer, and 4 additional placentas were used for an endogenous control. The ex vivo isolated cotyledon human placental perfusion model was used. The reference compound antipyrine was used to determine the transport fraction and clearance index of the cytokines. The cytokines were added to either the maternal or fetal circulations, and samples were collected for 1 hour in a constant-flow open circulation. Cytokine levels were compared between the study and control placentas. Concentrations of the cytokines were measured by sandwich enzyme immunoassay. RESULTS: The clearance index for the maternal-fetal transfer of IL-1alpha and TNF-alpha was 0.001, suggesting minimal transfer to the fetal circulation. The clearance index for IL-6 was 0.30, indicating transfer to the fetal circulation. When the cytokines were added to the fetal circulation, the clearance index for IL-1alpha was 0.001, again indicating minimal transfer. The clearance index for TNF-alpha in the fetal-maternal study was not determined. IL-6 had a clearance index of 0.23, which was similar to that observed with maternal-fetal transfer. IL-6 concentrations in the study placentas were higher than the concentrations found in the controls. CONCLUSION: There appears to be bidirectional transfer of IL-6 in the healthy-term human placental perfusion model. LEVEL OF EVIDENCE: II-2

Transplacental passage of vancomycin in the ex vivo human perfusion model.

OBJECTIVES: To determine maternal-fetal transplacental passage of vancomycin in the ex vivo human placental perfusion model. METHODS: Six term placentas were collected immediately after delivery and perfused with physiologic medium using the single cotyledon perfusion system. Vancomycin was added to the maternal medium and perfused through the maternal circulation of the cotyledon. Over a 1-h period in an open system, samples of the perfusate were collected at defined intervals from the fetal venous catheter and from the maternal effluence to assess vancomycin transfer. Thereafter, the system was closed for 1-5 h to establish accumulation. Transport fraction and clearance indexes were calculated by perfusing antipyrine 14C (positive control). Vancomycin was estimated by high pressure liquid chromatography and antipyrine 14C concentration was determined by liquid scintillation. RESULTS: Mean vancomycin maternal peak and trough concentrations ranged from 30.0 to 51.5 microg/ml and 7.7 to 16.4 microg/ml, respectively. Clearance indexes were minimal with a mean peak range of 0.000-0.080 and a mean trough range of 0.00-0.17. For each placenta, transport fraction for antipyrine 14C was > 1.85 with a single pass of > 40%. No accumulation of vancomycin was noted when the system was closed for 1-5 h. The mean peak clearance index was zero after perfusing the placenta for up to 5 h with 35.8 microg/ml of vancomycin. CONCLUSION: Transplacental passage of vancomycin was minimal in the ex vivo human placental perfusion model, with no detectable accumulation.

The bidirectional transfer and fetal vascular pressure changes due to the presence of 125I-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 inhibin A was 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 10(6) cpm/microg. 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.

Ex vivo human placental transfer of the peptides pramlintide and exenatide (synthetic exendin-4).

Two peptides, pramlintide (37 amino acids), an analog of human amylin, and exenatide, synthetic exendin-4 (39 amino acids), are both in late-stage clinical development as potential new treatments for people with diabetes. Both are potential long-term treatments, and there is the likelihood that some women will become pregnant while using one of these peptide therapies. Therefore, it was important to evaluate the potential for each peptide to cross the placental barrier and thereby result in exposure to the fetus. This was examined using ex vivo perfusions of human placentas. The fetal and maternal side of a cotyledon were cannulated and perfused first with buffer, and then with radioactive antipyrine in order to establish the integrity of the system and the perfusion constants. Either pramlintide or exenatide was then added to each acceptable cotyledon perfusate on the maternal side. Each peptide was evaluated at an initial concentration near the therapeutic plasma concentration and at approximately 10-50 times that concentration in each of the three cotyledons. Maternal and fetal perfusate samples were assayed for peptide concentrations using an immunoassay. The ratio of fetal-to-maternal peptide concentrations during equilibrium perfusion were extremely low (pramlintide < or = 0.006, exenatide < or = 0.017). These data demonstrate negligible passage of either peptide across the placental barrier. It is, therefore, likely that maternal use of either peptide during gestation will result in negligible exposure to the fetus.

Oxytocin preparation stability in several common obstetric intravenous solutions.

OBJECTIVE: The purpose of this study was to determine the stability of oxytocin in lactated Ringer's solution and lactated Ringer's-dextrose 5% solution over a 24-hour period at 25 degrees C and over a 7-day period at 5 degrees C. STUDY DESIGN: Twenty units (2.1 microg equal 1 unit) of oxytocin were injected into 1000 mL of lactated Ringer's solution and lactated Ringer's-dextrose 5% solution. Samples for the analysis were drawn at specified times after storage at 5 degrees C and 25 degrees C. These samples were stored at -70 degrees C for later analysis. Statistical analysis was done with 1-way analysis of variance and Tukey-Kramer multiple comparisons. RESULTS: Twenty units of oxytocin in 1000 mL of lactated Ringer's solution and lactated Ringer's-dextrose 5% solution was found to be stable for 7 days at 5 degrees C and for 24 hours at 25 degrees C. CONCLUSION: Premixed oxytocin solutions in lactated Ringer's solution and lactated Ringer's-dextrose 5% solution are stable in conditions commonly found in dispensing pharmacies and labor and delivery units. This finding could lead to the more efficient use of personnel during the mixing process, could provide solutions that are aseptically prepared, and could be a tool to reduce costs and improve patient care.