Development and validation of HPLC-ultraviolet method for quantitative determination of pritelivir in human placental perfusion medium.

A simple and reliable HPLC-ultraviolet (HPLC-UV) method was developed and validated for the quantification of pritelivir in the samples of medium from the experiments utilizing the ex vivo technique of dual perfusion of the human placental lobule. Phenacetin was used as an internal standard (IS) in our HPLC-UV method. Chromatographic separation of pritelivir and phenacetin was achieved on a Waters Symmetry C HPLC column (100 × 2.

Folate-mediated Transport of Nanoparticles across the Placenta.

Background: In this study, a prototype of a targeted nanocarrier for drug delivery for prenatal therapy of the developing fetus was developed and examined and ex vivo. The folate transport mechanism in the human placenta was utilized as a possible pathway for the transplacental delivery of targeted nanoparticles.

Methods: Several types of folic acid-decorated polymeric nanoparticles were synthesized and characterized.

Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone.

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d-methadone. The pharmacokinetic profiles of d-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.

Physicochemical and Biological Properties of Membrane Vesicles Derived from Human Term Placentas.

The purpose of this study was to conduct initial characterization of membrane vesicles isolated from human placenta by agitation of villous tissue (apical and basal) as well as vesicles obtained following dual perfusion of placental lobule. The morphology, physical and biological properties of the isolated vesicles were determined by electron microscopy, dynamic light scattering, and immunoblotting as well as nanoflow liquid chromatography-mass spectrometry proteomics analysis. CD-1 male mice were used to test the biocompatibility of the vesicles and assess the biodistribution of fluorescently labeled apical and perfusion vesicles.

Role of Uptake Transporters OAT4, OATP2A1, and OATP1A2 in Human Placental Bio-disposition of Pravastatin.

Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of potential undesirable fetal effects. The purpose of this study was to identify the uptake transporters that contribute to the placental disposition of pravastatin.

Formulation effects on paclitaxel transfer and uptake in the human placenta.

Diagnosis and treatment of breast cancer in pregnancy can result in morbidity and mortality for the mother and fetus. Many new paclitaxel nanoformulations commercially available worldwide for breast cancer treatment are being adopted due to favorable dosing regimens and side effect profiles, but their transplacental transport and resultant fetal exposure remain unknown. Here, we examine three formulations: Taxol (paclitaxel dissolved in Kolliphor EL and ethanol); Abraxane (albumin nanoparticle); and Genexol-PM (polymeric micelle).

M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model.

Background: The transfer of pathogenic immunoglobulin G antibodies from mother to fetus is a critical step in the pathophysiology of alloimmune and autoimmune diseases of the fetus and neonate. Immunoglobulin G transfer across the human placenta to the fetus is mediated by the neonatal Fc receptor, and blockade of the neonatal Fc receptor may provide a therapeutic strategy to prevent or minimize pathological events associated with immune-mediated diseases of pregnancy. M281 is a fully human, aglycosylated monoclonal immunoglobulin G1 antineonatal Fc receptor antibody that has been shown to block the neonatal Fc receptor with high affinity in nonclinical studies and in a phase 1 study in healthy volunteers.

Determination of the Transplacental Transfer of Paclitaxel and Antipyrine by High Performance Liquid Chromatography Coupled with Photodiode Array Detector.

placental perfusion experiments are important in understanding the quantity and mechanisms of xenobiotic transport to the fetus during pregnancy. Our study demonstrates that paclitaxel and antipyrine concentrations in placental perfusion medium containing physiological concentrations of human serum albumin during pregnancy (30 mg/mL) can be quantified by RP-HPLC and UV detection. A liquid-liquid extraction method was developed for the quantification of paclitaxel and celecoxib (internal standard) from perfusion medium.

Role of the efflux transporters BCRP and MRP1 in human placental bio-disposition of pravastatin.

The expression and activity of human placental transporters during pregnancy could be altered by several factors including pathological changes associated with preeclampsia. The aims of this study were to identify the placental efflux transporters involved in the bio-disposition of pravastatin, determine the protein expression of these transporters and their encoding genes as well as the activity of pravastatin uptake in placentas obtained from patients with preeclampsia. ATP-dependent uptake of [3H]-pravastatin by trophoblast tissue apical and basal membrane vesicles exhibited sigmoidal kinetics.

The Role of Placental Carbonyl Reducing Enzymes in Biotransformation of Bupropion and 4-methylnitrosamino-1-(3-pyridyl)-1-butanone.

Background: Bupropion (BUP) has a potential to be an effective pharmacotherapy for smoking cessation during pregnancy. Smoking during pregnancy stimulates placental carbonyl reductases that catalyze the biotransformation of BUP. 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen of cigarette smoke.

Transplacental transfer and distribution of pravastatin.

Objective: The objective of the study was to determine the bidirectional transfer of pravastatin across the dually perfused term human placental lobule and its distribution between the tissue and maternal and fetal circuits.

Study Design: The transfer of pravastatin was determined in the maternal-to-fetal (n = 11) and fetal-to-maternal (n = 10) directions. Pravastatin was coperfused with its [(3)H]-isotope and the marker compound antipyrine (20 μg/mL) and its [(14)C]-isotope.

Transplacental transfer of vancomycin and telavancin.

Objective: We sought to determine the bidirectional transfer and distribution of vancomycin and telavancin across the dually perfused term human placental lobule.

Study Design: The technique of dually perfused placental lobule was used in its recirculating mode to determine the maternal to fetal (M→F) (n = 20) and fetal to maternal (n = 18) transfer of each antibiotic, which were coperfused with their radioactive isotopes. The concentrations of drugs were determined by liquid scintillation spectrometry.

Transplacental transfer of oseltamivir carboxylate.

Objectives: Determine the bidirectional transfer of oseltamivir carboxylate (OC) across term human placenta and its distribution between the tissue, maternal and fetal circuits.

Methods: The technique of dual perfusion of placental lobule (DPPL) in its recirculating mode was utilized to determine the transfer of the drug. OC (350 ng/mL) was co-perfused with its [(3)H]-isotope and the marker compound antipyrine (AP, 20 µg/mL) together with its [(14)C]-isotope.

Transplacental transfer and metabolism of buprenorphine in preterm human placenta.

We sought to determine whether gestational age affects the transplacental transfer and metabolism of buprenorphine (BUP). Transfer of BUP (10 ng/mL) and its [ (3)H]-isotope was determined across placentas of 30 to 34 weeks of gestation utilizing the technique of dual perfusion of placental lobule. Concentration of the drug in trophoblast tissue and in maternal and fetal circuits was determined by liquid scintillation spectrometry.

Role of transporter-mediated efflux in the placental biodisposition of bupropion and its metabolite, OH-bupropion.

Cigarette smoking during pregnancy is a preventable risk factor associated with maternal and fetal complications. Bupropion is an antidepressant used successfully for smoking cessation in non-pregnant patients. Our goal is to determine whether it could benefit the pregnant patient seeking smoking cessation.

Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin.

Objective: Substrates of placental efflux transporters could compete for a single transporter, which could result in an increase in the transfer of each substrate to the fetal circulation. Our aim was to determine the role of placental transporters in the biodisposition of oral hypoglycemic drugs that could be used as monotherapy or in combination therapy for gestational diabetes.

Study Design: Inside-out brush border membrane vesicles from term placentas were used to determine the efflux of glyburide, rosiglitazone, and metformin by P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein.

Bupropion metabolism by human placenta.

Smoking during pregnancy is the largest modifiable risk factor for pregnancy-related morbidity and mortality. The success of bupropion for smoking cessation warrants its investigation for the treatment of pregnant patients. Nevertheless, the use of bupropion for the treatment of pregnant smokers requires additional data on its bio-disposition during pregnancy.

Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms.

The ABC transporter P-glycoprotein is a product of the MDR1 gene and its function in human placenta is to extrude xenobiotics from the tissue thus decreasing fetal exposure. The goal of this investigation was to examine the effect of three polymorphisms in the MDR1 gene on the expression and activity of placental P-gp. In 199 term placentas examined, the C1236T variant was associated with 11% lower P-gp protein expression than wild-type, while the C3435T and G2677T/A variants each were associated with a 16% reduction (p<0.

Transplacental transfer and metabolism of bupropion.

Objective: In order to evaluate the potential use of bupropion as smoking cessation therapy during pregnancy, the aim of this investigation was to determine transplacental transfer and metabolism of bupropion and its distribution among placental tissue and maternal and fetal circuits of the dually perfused placental lobule.

Methods: Placentas obtained from healthy term pregnancies were perfused with bupropion at two concentrations 150 ng/ml and 450 ng/ml, along with the marker compound antipyrine 20 microg/ml. Radioactive isotopes of the two drugs were co-transfused to enhance their detection limits.

Opiates inhibit paclitaxel uptake by P-glycoprotein in preparations of human placental inside-out vesicles.

The use of either methadone or buprenorphine for treatment of the pregnant opiate-dependent patient improves maternal and neonatal outcome. However, patient outcomes are often complicated by neonatal abstinence syndrome (NAS). The incidence and severity of NAS should depend on opiate concentration in the fetal circulation.

Effect of plasma proteins on buprenorphine transfer across dually perfused placental lobule.

Objective: The aim of this investigation is to determine the effect of human serum albumin (HSA) and alpha-acid glycoprotein (AAG) on buprenorphine (BUP) transplacental transfer and distribution.

Methods: The technique of dual perfusion of placental lobule (DPPL) was utilised. BUP was co-perfused with the marker compound antipyrine (AP).

Transplacental transfer and metabolism of 17-alpha-hydroxyprogesterone caproate.

Objective: Determine transplacental transfer and metabolism of 17-alpha-hydroxyprogesterone caproate and its distribution between the tissue and the maternal and fetal circuits of the dually perfused placental lobule.

Study Design: 17-alpha-Hydroxyprogesterone caproate (21 ng/mL) and its dual-labeled isotope, 17-alpha-hydroxy-[(3)H] progesterone [(14)C] caproate were added to the maternal circuit. The concentrations of the drug and its metabolite in trophoblast tissue and both circuits were determined by high performance liquid chromatography and liquid scintillation spectrometry.

Effect of albumin on transplacental transfer and distribution of rosiglitazone and glyburide.

Objective: The aims of this investigation were (i) to determine the rate and extent of rosiglitazone transfer across term human placenta, and (ii) to determine the effect of human serum albumin (HSA) on rosiglitazone and glyburide transfer and distribution.

Methods: These aims were achieved by utilizing the technique of dual perfusion of placental lobule (DPPL). Each hypoglycemic drug was coperfused with the marker compound antipyrine (AP).

Transfer of metformin across the dually perfused human placental lobule.

Objective: The purpose of this study was to determine the transfer characteristics of metformin across placentas that were obtained from uncomplicated pregnancies and from patients with gestational diabetes mellitus.

Study Design: The technique of dual perfusion of placental lobule was used. Metformin, 5 microg/mL and its [14C]-isotope were co-transfused with the marker compound antipyrine, 20 microg/mL and its [3H]-isotope from the maternal to fetal circuit.