Dataset Information

Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model.

ABSTRACT:

Objective

To determine the transplacental pharmacokinetics of the HIV integrase inhibitor dolutegravir.

Study design

Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in 5 closed-circuit, recirculating experiments. Dolutegravir was added to a maternal perfusate containing antipyrine, a marker to validate the cotyledon's viability, and 2 g/liter of human albumin.

Results

After 3h of recirculating perfusion, the mean (± SD) DTG concentrations in the maternal and in the fetal compartments were respectively 2450 ± 286 ng/mL and 715 ± 369 ng/mL, with a fetal-to-maternal ratio of 34% ± 18% and a clearance index (in comparison with antipyrine transfer) of 79% ± 23%. The mean cotyledon accumulation index was 153% ± 25%.

Conclusion

Fetal transplacental exposure to dolutegravir was considerable as well as accumulation in placental tissue. Whether this may lead to risks for the exposed fetus requires more investigation.

SUBMITTER: Mandelbrot L

PROVIDER: S-EPMC6692001 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model.

Mandelbrot Laurent L Ceccaldi Pierre-François PF Duro Dominique D Lê Minh M Pencolé Lucile L Peytavin Gilles G

PloS one 20190813 8

<h4>Objective</h4>To determine the transplacental pharmacokinetics of the HIV integrase inhibitor dolutegravir.<h4>Study design</h4>Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in 5 closed-circuit, recirculating experiments. Dolutegravir was added to a maternal perfusate containing antipyrine, a marker to validate the cotyledon's viability, and 2 g/liter of human albumin.<h4>Results</h4>After 3h of recirculating perf ...[more]

PMID: 31408460

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Project description:BACKGROUND:Exposure to maternal stress during pregnancy can have adverse effects on the fetus, which has potential long-term effects on offspring´s development and health. We investigated the kinetics and metabolism of the hormones and amino acids: cortisol, cortisone, tryptophan and serotonin in the term placenta in an ex vivo human placental perfusion model. The placentas used in the experiments were donated from families participating in the Maternal Stress and Placental Function project with a known maternal stress background. METHOD:Cortisol, cortisone, tryptophan and serotonin were added simultaneously to the maternal side in the 6 hour ex vivo term human recirculating placental perfusion model, in four experimental set-ups: without inhibitors, with carbenoxolone -that inhibits cortisol metabolism into cortisone, with fluoxetine that inhibits the serotonin transporter, and with PCPA that inhibits metabolism of tryptophan into serotonin. The concentration of cortisol and cortisone, and tryptophan and serotonin were quantified using UPLC and HPLC-MS respectively. RESULTS:Cortisol was rapidly metabolized into cortisone in the placenta, to a somewhat lesser degree when adding the inhibitor carbenoxolone, resulting in higher fetal exposure to cortisol. Serotonin was also rapidly metabolized in the placenta. When adding fluoxetine a peak of fetal serotonin levels was seen in the first hour of the perfusion. No effect was seen of the maternal stress levels on placental transport kinetics in this study. CONCLUSION:Inhibiting the metabolism of cortisol in the placenta increased fetal exposure to cortisol as expected. Unexpectedly we saw an increased fetal exposure to serotonin when inhibiting the serotonin transporter, which may be related to the increased serotonin concentration on the maternal side of the placenta. No effect on placental kinetics were evident on maternal stress levels during the pregnancy as the majority of participating mothers had normal stress levels.

Dataset Information

Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model.

Objective

Study design

Results

Conclusion

Publications

Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model.

Similar Datasets

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