The acquired immunodeficiency syndrome (AIDS) is a devastating disease which has now reached epidemic proportions in the United States. The causative agent, the human immunodeficiency virus (HIV), can be transmitted by several routes. Of these, the route of maternal-fetal transmission is the most important contributor to the increase in incidence of HIV infection in children. It is estimated that by 1992 AIDS is likely to be one of the five leading causes of mortality in the 1-4 year age group. Currently only one drug, zidovudine (ZDV or azidothymidine), a dideoxynucleoside (ddNS), has been approved for use in the treatment of adult AIDS patients. Several other dideoxynucleosides (ddNSs) are currently undergoing phase I or II trials. However, none of these drugs are currently approved for administration to HIV infected pregnant women. The long-term objective of the proposed project is to test the hypothesis that administration of anti-HIV drugs to HIV positive pregnant women may either reduce the incidence of maternal-fetal transmission of the HIV or retard the onset and course of AIDS in the offspring. Before testing this hypothesis, studies need to be conducted in a representative animal model to ascertain if anti-HIV drugs can cross the placenta and if so whether they are capable of accumulating in the fetus.
The specific aims of this project, therefore,are: 1 .To determine the transplacental pharmacokinetics of four dideoxynucleosides of varying lipophilicity, namely zidovudine (ZDV), dideoxycytidine (DDC), dideoxyinosine (DDI) and didehyro-dideoxythymidine (D4T) in a chronically catheterized maternal-fetal macaque (Macaca nemestrina) model. 2.To determine the mutual interaction between ZDV and DDC, DDI or D4T with respect to their transplacental pharmacokinetics in the above macaque model. 3.To determine the transplacental pharmacokinetics of the above listed dideoxynucleosides in the (in vitro) isolated perfused human placenta model. 4.To determine the ability of the in vitro perfused human placenta to predict the in vivo transplacental pharmacokinetics of the ddNSs in the macaque.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027438-04
Application #
2200425
Study Section
Special Emphasis Panel (SRC (10))
Project Start
1991-02-01
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Washington
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Tuntland, T; Odinecs, A; Pereira, C M et al. (1999) In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol 180:198-206
Tuntland, T; Odinecs, A; Nosbisch, C et al. (1998) In vivo maternal-fetal-amniotic fluid pharmacokinetics of zidovudine in the pigtailed macaque: comparison of steady-state and single-dose regimens. J Pharmacol Exp Ther 285:54-62
Patil, S D; Unadkat, J D (1997) Sodium-dependent nucleoside transport in the human intestinal brush-border membrane. Am J Physiol 272:G1314-20
Chandrasena, G; Giltay, R; Patil, S D et al. (1997) Functional expression of human intestinal Na+-dependent and Na+-independent nucleoside transporters in Xenopus laevis oocytes. Biochem Pharmacol 53:1909-18
Tuntland, T; Nosbisch, C; Unadkat, J D (1997) Effect of pregnancy, mode of administration and neonatal age on the pharmacokinetics of zalcitabine (2', 3'-dideoxycytidine) in the pigtailed macaque (Macaca nemestrina). J Antimicrob Chemother 40:687-93
Tuntland, T; Nosbisch, C; Baughman, W L et al. (1996) Mechanism and rate of placental transfer of zalcitabine (2',3'-dideoxycytidine) in Macaca nemestrina. Am J Obstet Gynecol 174:856-63
Odinecs, A; Pereira, C; Nosbisch, C et al. (1996) Prenatal and postpartum pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother 40:2423-5
Odinecs, A; Nosbisch, C; Keller, R D et al. (1996) In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother 40:196-202
Odinecs, A; Nosbisch, C; Unadkat, J D (1996) Zidovudine does not affect transplacental transfer or systemic clearance of stavudine (2',3'-didehydro-3'-deoxythymidine) in the pigtailed macaque (Macaca nemestrina). Antimicrob Agents Chemother 40:1569-71

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