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. 1996 Jan;40(1):196–202. doi: 10.1128/aac.40.1.196

In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macaca nemestrina).

A Odinecs 1, C Nosbisch 1, R D Keller 1, W L Baughman 1, J D Unadkat 1
PMCID: PMC163082  PMID: 8787905

Abstract

To determine whether stavudine (2',3'-didehydro-3'-deoxythymidine) is actively transported in vivo across the placenta and to determine the extent of its transfer, stavudine was administered as an intravenous bolus to four near-term macaques (Macaca nemestrina) (5 mg/kg of body weight via the femoral vein) or to their fetuses (10 mg/kg via the carorid artery) at gestational age 134 +/- 5 days, with the administrations about 1 week apart. Antipyrine (a passive diffusion marker) was always coadministered (20 mg/kg) with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at frequent intervals up to 240 min after the dose. In a separate experiment, three animals received stavudine for 30 h at a low rate of infusion (22 micrograms/min/kg via the femoral vein) to the dam or at a 10-fold-higher rate of infusion (220 micrograms/min/kg), separated by at least one week, in order to determine if the transplacental transfer of stavudine is saturable. Antipyrine (41.7 micrograms/min/kg) was coinfused with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at regular intervals for up to 30 h. The concentrations of stavudine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student t test. The clearance associated with maternal-fetal transfer of the drug (CLdf) (0.54 +/- 0.08 ml/min/kg) was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.66 +/- 0.11 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.23 +/- 0.04 versus 0.36 +/- 0.25). The ratios of the steady-state plasma stavudine concentration in the fetus to that in the dam were 0.77 +/- 0.06 at the low stavudine infusion rate and 0.81 +/- 0.09 at the high stavudine infusion rate. The obtained data indicate that transfer of stavudine across the placenta is passive and constant over the dose range studied.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. August E. M., Birks E. M., Prusoff W. H. 3'-Deoxythymidin-2'-ene permeation of human lymphocyte H9 cells by nonfacilitated diffusion. Mol Pharmacol. 1991 Feb;39(2):246–249. [PubMed] [Google Scholar]
  2. Bawdon R. E., Kaul S., Sobhi S. The ex vivo transfer of the anti-HIV nucleoside compound d4T in the human placenta. Gynecol Obstet Invest. 1994;38(1):1–4. doi: 10.1159/000292432. [DOI] [PubMed] [Google Scholar]
  3. Connor E. M., Sperling R. S., Gelber R., Kiselev P., Scott G., O'Sullivan M. J., VanDyke R., Bey M., Shearer W., Jacobson R. L. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 3;331(18):1173–1180. doi: 10.1056/NEJM199411033311801. [DOI] [PubMed] [Google Scholar]
  4. Delfraissy J. F., Blanche S., Rouzioux C., Mayaux M. J. Perinatal HIV transmission facts and controversies. Immunodefic Rev. 1992;3(4):305–327. [PubMed] [Google Scholar]
  5. Duenhoelter J. H., Pritchard J. A. Fetal respiration: quantitative measurements of amnionic fluid inspired near term by human and rhesus fetuses. Am J Obstet Gynecol. 1976 Jun 1;125(3):306–309. doi: 10.1016/0002-9378(76)90564-0. [DOI] [PubMed] [Google Scholar]
  6. Kaul S., Dandekar K. A. Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys. Antimicrob Agents Chemother. 1993 May;37(5):1160–1162. doi: 10.1128/aac.37.5.1160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Lin T. S., Schinazi R. F., Prusoff W. H. Potent and selective in vitro activity of 3'-deoxythymidin-2'-ene (3'-deoxy-2',3'-didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol. 1987 Sep 1;36(17):2713–2718. doi: 10.1016/0006-2952(87)90253-x. [DOI] [PubMed] [Google Scholar]
  8. Lopez-Anaya A., Unadkat J. D., Schumann L. A., Smith A. L. Pharmacokinetics of zidovudine (azidothymidine). I. Transplacental transfer. J Acquir Immune Defic Syndr. 1990;3(10):959–964. [PubMed] [Google Scholar]
  9. Morton W. R., Knitter G. H., Smith P. M., Susor T. G., Schmitt K. Alternatives to chronic restraint of nonhuman primates. J Am Vet Med Assoc. 1987 Nov 15;191(10):1282–1286. [PubMed] [Google Scholar]
  10. Novy M. J., Thomas C. L., Lees M. H. Uterine contractility and regional blood flow responses to oxytocin and prostaglandin E2 in pregnant rhesus monkeys. Am J Obstet Gynecol. 1975 Jun 15;122(4):419–433. doi: 10.1016/s0002-9378(16)33533-5. [DOI] [PubMed] [Google Scholar]
  11. Ochs H. D., Morton W. R., Tsai C. C., Thouless M. E., Zhu Q., Kuller L. D., Wu Y. P., Benveniste R. E. Maternal-fetal transmission of SIV in macaques: disseminated adenovirus infection in an offspring with congenital SIV infection. J Med Primatol. 1991 Jun;20(4):193–200. [PubMed] [Google Scholar]
  12. Pereira C. M., Nosbisch C., Winter H. R., Baughman W. L., Unadkat J. D. Transplacental pharmacokinetics of dideoxyinosine in pigtailed macaques. Antimicrob Agents Chemother. 1994 Apr;38(4):781–786. doi: 10.1128/aac.38.4.781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ravasco R. J., Unadkat J. D., Tsai C. C., Nosbisch C. Pharmacokinetics of dideoxyinosine in pigtailed macaques (Macaca nemestrina) after intravenous and subcutaneous administration. J Acquir Immune Defic Syndr. 1992 Oct;5(10):1016–1018. [PubMed] [Google Scholar]
  14. Schinazi R. F., Boudinot F. D., Doshi K. J., McClure H. M. Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rhesus monkeys. Antimicrob Agents Chemother. 1990 Jun;34(6):1214–1219. doi: 10.1128/aac.34.6.1214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Schmidt W. The amniotic fluid compartment: the fetal habitat. Adv Anat Embryol Cell Biol. 1992;127:1–100. doi: 10.1007/978-3-642-77300-6. [DOI] [PubMed] [Google Scholar]

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