Placental transfer and metabolism: An overview of the experimental models utilizing human placental tissue

Myllynen, Päivi; Vähäkangas, Kirsi

doi:10.1016/j.tiv.2012.08.027

Cited by 95 publications

(101 citation statements)

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“…Nonetheless, the procedure is carefully monitored and standardized to approach mimicking normal 40 10 52 544 37 7 13 262 67 26 38 423 44 10 44 30 217 45 21 64 399 62 16 26 249 82 33 47 400 92 23 47 45 622 76 12 31 463 86 19 29 375 78 21 26 400 162 41 71 60 598 50 8 23 410 105 26 45 243 79 33 42 420 96 23 42 75 210 65 31 139 404 86 21 33 314 77 25 29 387 90 23 101 90 341 75 22 61 387 118 30 59 304 106 35 58 340 110 32 physiology, and the FTR of antipyrine is monitored in order to control the integrity of the placental barrier. The results obtained with this ex vivo placental perfusion model have been found to be consistent with in vivo findings for a number of compounds, including antiretroviral agents (7,8).…”

Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphensupporting

confidence: 81%

“…A number of adverse events have been reported following perinatal exposure to antiretroviral medications, including mitochondrial diseases (6). Since data from animal studies are difficult to extrapolate to humans due to differences in placental physiology, other preclinical approaches are required.The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.…”

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confidence: 99%

“…The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.…”

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confidence: 99%

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Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Mandelbrot

Duro

Belissa

et al. 2015

Antimicrob Agents Chemother

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e Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ؎ 8% (mean ؎ standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ؎ 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.A ntiretroviral drugs are remarkably effective for preventing vertical transmission of HIV-1, resulting in a decline in the rate of transmission, which is now less than 0.5% in France (1, 2). Current guidelines recommend antiretroviral therapy for all HIVinfected pregnant women for their own health and to prevent transmission (3, 4)., a diarylpyrimidine analog, is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which is increasingly used to treat HIV infection and in recent guidelines is considered a first-line treatment. It is available in a single-tablet formulation in combination with tenofovir and emtricitabine (Complera-Eviplera). Rilpivirine is classified as a pregnancy category B drug by the Food and Drug Administration (4), which means that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in HIV-1-infected pregnant women. To date, only one report has been published on two cases of rilpivirine use in pregnant women (5), in which the plasma concentrations of rilpivirine were lower than would be expected in nonpregnant women. Placental transfer was studied in one of these two cases. Currently, there are no data on the safety of rilpivirine use during pregnancy.Determining fetal exposure is important for all new medications in order to estimate the potential for preexposure prophylaxis and the risk for toxicities to the fetus. A number of adverse events have been reported following perinatal exposure to antiretroviral medications, including mitochondrial diseases (6). Since data from animal studies are difficult to extrapolate to humans due to differences in placental physiology, other preclinical approaches are required.The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.Placentas were collected after uncomplicated pregnancy with full-term delivery (Ն37 weeks gestational age) in mothers who were seronegative for HIV and hepatitis B and C viruses and had taken no medication, except for vitamin supplements and perimedullar analgesia. They were collected in a single center, the maternity ward of the Hôpitaux Universitaires Paris-Nord Val de Seine (Colombes, France), and were rapidly perfused on site. Written informed consent was obtained from each of the women who donated a placenta, acc...

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Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphensupporting

confidence: 81%

mentioning

confidence: 99%

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Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Mandelbrot

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Belissa

et al. 2015

Antimicrob Agents Chemother

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“…Placenta provides a gateway to oxygen and nutrients from mother to fetus, produces hormones to support the pregnancy and serves as an excretion pathway for various metabolites; it plays an important role in the exposure of the fetus to potential toxicants via maternal circulation (Myllynen & V€ ah€ akangas, 2013). Nicotine rapidly crosses the placental membrane into the fetal bloodstream (Lips et al, 2005), the blood-testis barrier (Zenzes, 2000), and is present in breast milk of nicotine-exposed rats (Paccola et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Late reproductive analysis in rat male offspring exposed to nicotine during pregnancy and lactation

et al. 2016

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SUMMARYWe previously observed that nicotine, administered to rats (Wistar) during pregnancy and lactation periods, provokes, in the progeny, late morphofunctional alterations in Leydig cell, body weight increase in adulthood (90 days post partum, dpp) as well as seminiferous epithelium injury. Aiming to investigate whether the spermatogenic damage previously observed in adult progenies from pregnant and lactating nicotine-exposed rat dams are maintained or whether it is worsened in older rats, we analyzed the morphological testicular alterations after up to two complete periods of spermatogenesis (53 days each), spermatic parameters, and sperm DNA fragmentation. Pregnant and lactating rats were nicotine-exposed (2 mg/kg/day) through an osmotic minipump implanted on the first day of pregnancy and replaced after birth. Absolute Control (no minipump) and Sham Control (minipump without nicotine) groups were established. The offspring were killed at 90, 143, and 196 dpp. Significant alterations in morphometric and stereological testicular parameters, such as concentration of sperm number, daily sperm production, and plasma and intratesticular levels of cholesterol and testosterone were not observed in nicotine-exposed rats. Testicular histopathological analysis showed small intraepithelial vacuolization and an accentuated germ cell desquamation in exposed rats. However, the offspring from nicotine-exposed dams exhibited higher frequency of morphologically abnormal spermatozoa and lower sperm motility in comparison with control groups. In addition, nicotine-exposed groups showed a significant reduction in sperm mitochondrial activity and an increased sperm DNA fragmentation (Comet assay). These results indicate a late reproductive damage in the male progeny caused by maternal nicotine exposure, related to the decrease in sperm quality.

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“…The ex vivo human placenta perfusion model is an effective and non-invasive method to study transplacental passage of drugs and environmental com-pounds in humans 2. It is the only method that retains the full structure of a full term human placenta, making it possible to study transplacental passage without harm-ing the foetus or the mother 3. Due to many challenges and its high complexity it remains difficult to incorporate it routinely into laboratories.…”

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confidence: 99%

PP-6 Integration and validation of the ex vivo human placenta perfusion model

et al. 2017

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BackgroundPregnant women and their fetuses are or-phan populations with respect to knowledge on safety and efficacy of drugs. It is estimated that over 90% of pregnant women uses over-the-counter or prescription medication.1 Albeit, data on transplacental transfer or fetal effects are still lacking for most of the medicines and food supplements. The ex vivo human placenta perfusion model is an effective and non-invasive method to study transplacental passage of drugs and environmental com-pounds in humans.2 It is the only method that retains the full structure of a full term human placenta, making it possible to study transplacental passage without harm-ing the foetus or the mother.3 Due to many challenges and its high complexity it remains difficult to incorporate it routinely into laboratories.MethodsA step-by-step protocol for the implementa-tion and validation of a closed-closed ex vivo perfusion model was developed. Different quality controls were implemented to ensure the integrity, viability and func-tionality of the method: (i). Antipyrine is a small drug molecule that does not bind to proteins and that passes the placental barrier by passive diffusion; It was used here to determine ‘overlap’ (solute exchange) between foetal and maternal circulation; (ii) the pressure and the flow rate in the foetal circulation as a marker for leakage; (iii) pH and glucose consumption were implemented as a marker for tissueviability.ResultsIn total 89 placentas were collected of which 34 placentas were successfully perfused with antipyrine and fulfilled all quality control measurements. A foe-tal/maternal antipyrine concentration ratio of 0.75 was reached within 89±21 min, while 210 min were required to achieve equilibrium. The foetal pressure remained un-der 70 mmHg during the entire experiment. The end foe-tal flow was 98% of the foetal starting flow. The average glucose consumption was 0.30±0.15 µmol/min/g. Every 30 min the maternal pH declined to 7.29±0.06 and was adjusted to 7.4. The foetal pH stayed stable at 7.30±0.05.ConclusionBased on the multiple quality control mea-surements, the described method of a closed human ex-vivo placenta perfusion model was validated. The success rate (38%) was more than twice the success rate reported in literature (15%).

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Placental transfer and metabolism: An overview of the experimental models utilizing human placental tissue

Cited by 95 publications

References 55 publications

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Late reproductive analysis in rat male offspring exposed to nicotine during pregnancy and lactation

PP-6 Integration and validation of the ex vivo human placenta perfusion model

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