In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus☆,☆☆,★
Section snippets
In vivo catheterized pregnant macaque model
Each of the 4 drugs was tested in 3 or 4 near-term pregnant pigtailed macaques. The protocol for the care and use of the animals was approved by the University of Washington Institutional Animal Care and Use Committee. The experimental design and data analyses of dideoxynucleoside studies in our laboratory are described elsewhere.1, 2, 3, 4, 5, 6, 7, 8, 9 Briefly, the macaques underwent long-term catheterization at 125 to 130 days of gestation. With the animals under general anesthesia,
Results
The mechanism of placental transfer of zidovudine, stavudine, zalcitabine, and didanosine was found to be passive in both the in vivo pregnant macaque model and the in vitro perfused human placenta model. The rates of placental transfer (clearance indexes) determined in vivo and in vitro were significantly correlated with each other (r 2 = 0.93, P < .05; Fig 1).
Comment
We chose the pigtailed macaque as a representative animal model primarily because it has a discoid placenta with multivillous fetal-maternal interdigitation and a hemo-monochorionic barrier similar to that found in humans. In addition, the disposition of dideoxynucleosides in the macaque is comparable to that in humans,1, 2, 3, 4, 5, 6, 7, 8, 9 and both HIV-2 and the simian immunodeficiency virus can be transmitted from the mother to the fetus in this animal species. Therefore the macaque may
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Stavudine exposure results in developmental abnormalities by causing DNA damage, inhibiting cell proliferation and inducing apoptosis in mouse embryos
2020, ToxicologyCitation Excerpt :C57BL/6 mice (11400500030643, 9–10 weeks, 18–23 g) were housed in specific pathogen-free (SPF) cages at an approved facility on a 12 h light/dark cycle and with controlled temperature (22℃) and humidity (40–60 %). Mouse embryos at GD8.5 (Causeret et al., 2016) were cultured under sterilized condition at 37℃ for 48 h in heat-inactivated rat serum (Tuntland et al., 1999). Stavudine was bought from MCE (Med Chem Express) and the catalogs number was # 3056-17-5.
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Supported by grants HD27438, HD02274, and RR00166 from the National Institutes of Health.
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Reprint requests: Jashvant D. Unadkat, PhD, Professor, Department of Pharmaceutics, Box 357610, School of Pharmacy, University of Washington, Seattle, WA 98195-7610.
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0002-9378/99 $8.00 + 0 6/1/93227