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Mechanism and rate of placental transfer of zalcitabine (2',3'-dideoxycytidine) in Macaca nemestrina

      Abstract

      OBJECTIVE: Our purpose was to determine whether the anti-human immunodeficiency virus drug zalcitabine (2',3'-dideoxycytidine) is actively transferred across the placenta in the near-term Macaca nemestrina.STUDY DESIGN: Constant rate infusions of zalcitabine (1.31 μg/min/kg) and antipyrine (66.7 μg/min/kg) were administered to the dam through the femoral vein (n = 4) or to the fetus through the carotid artery (n = 3) in a randomized cross-over design. Zalcitabine was also administered at a 10-fold higher infusion rate to the dam (n = 3). The effect of zidovudine on the transplacental transfer of zalcitabine was studied by coinfusing the two drugs to the dam (n = 2). Samples from maternal plasma, fetal plasma, and amniotic fluid were collected at regular intervals during the 30-hour infusions. RESULTS: The maternal-fetal transfer clearance of zalcitabine (0.41 ± 0.16 ml/min/kg) was not significantly different from the fetal-maternal transfer clearance of the drug (0.66 ± 0.30 ml/min/kg). Moreover, the steady-state fetal-maternal plasma concentration ratios of zalcitabine after the low (0.58 ± 0.06) and high (0.66 ± 0.10) infusion rates to the dam were similar. This ratio was not substantially changed (0.69) when zalcitabine was coadministered with zidovudine. The placental transfer rate of zalcitabine was 11% (±4%) that of antipyrine. CONCLUSION: The placental transfer of zalcitabine is passive and unaffected by simultaneous administration of zidovudine. In Macaca nemestrina the average fetal exposure to zalcitabine is approximately 60% of the maternal exposure. (AM J OBSTET GYNECOL 1996;174:856-63.)

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      References

        • Griffith BP
        • Booss J.
        Neurologic infections of the fetus and newborn.
        Neurol Clin. 1994; 12: 541-564
        • Delfraissy JF
        • Blanche S
        • Rouzioux C
        • Mayaux MJ.
        Perinatal HIV transmission: facts and controversies.
        Immunodefic Rev. 1992; 3: 305-327
        • Connor EM
        • Sperling RS
        • Gelber R
        • et al.
        Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment.
        N Engl J Med. 1994; 331: 1173-1180
        • Broder S
        Pharmacodynamics of 2',3'-dideoxycytidine: an inhibitor of human immunodeficiency virus.
        Am J Med. 1990; 88: 2S-7S
        • Toltzis P
        • Mourton T
        • Magnuson T.
        Comparative embryonic cyto-toxicity of antiretroviral nucleosides.
        J Infect Dis. 1994; 169: 1100-1102
        • Merigan TC
        • Skowron G
        • Bozzette SA
        • et al.
        Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections: a phase I and II study.
        Ann Intern Med. 1989; 110: 189-194
        • Meng T-C
        • Fischl MA
        • Boota AM
        • et al.
        Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immuno-deficiency virus infection: a phase I/II study.
        Ann Intern Med. 1992; 116: 13-20
        • Lopez-Anaya A
        • Unadkat JD
        • Schumann LA
        • Smith AL.
        Pharmacokinetics of zidovudine (azidothymidine), I: transplacental transfer.
        J Acquir Immune Defic Syndr. 1990; 3: 959-964
        • Pereira CM
        • Nosbisch C
        • Winter HR
        • Baughman WL
        • Unadkat JD.
        Transplacental pharmacokinetics of dideoxyinosine in pigtailed macaques.
        Antimicrob Agents Chemother. 1994; 38: 781-786
        • Odinecs A
        • Nosbisch C
        • Keller RD
        • Baughman WL
        • Unadkat JD
        In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macacanemestrina).
        Antimicrob Agents Chemother. 1996; 40: 196-202
        • King BF.
        Morphology of the placenta and fetal membranes.
        in: Comparative primate biology: reproduction and development.3. Alan R Liss, New York1986: 311-331
        • Ravasco RJ
        • Unadkat JD
        • Tsai CC
        • Nosbisch C
        Pharmacokinetics of dideoxyinosine in pigtailed macaques (Macaca nemestrina) after intravenous and subcutaneous administration.
        J Acquir Immune Defic Syndr. 1992; 5: 1016-1018
        • Lopez-Anaya A
        • Unadkat JD
        • Schumann LA
        • Smith AL.
        Pharmacokinetics of zidovudine (azidothymidine), III: effect of pregnancy.
        J Acquir Immune Defic Syndr. 1991; 4: 64-68
        • Ochs HD
        • Morton WR
        • Tsai CC
        • et al.
        Maternal-fetal transmission of SIV in macaques: disseminated adenovirus infection in an offspring with congenital SIV infection.
        J Med Primatol. 1991; 20: 193-200
        • Klecker Jr, RW
        • Collins JM
        • Yarchoan RC
        • et al.
        Pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS and related diseases.
        J Clin Pharmacol. 1988; 28: 837-842
        • Gustavson LE
        • Fukuda EK
        • Rubio FA
        • Dunton AW
        A pilot study of the bioavailability and pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS or AIDS-related complex.
        J Acquir Immune Defic Syndr. 1990; 3: 28-31
        • Plagemann PGW
        • Woffendin C.
        Dideoxycytidine permeation and salvage by mouse leukemia cells and human erythrocytes.
        Biochem Pharmacol. 1989; 38: 3469-3475
        • Pajor AM
        • Wright EM
        Cloning and functional expression of a mammalian Na+/nucleoside cotransporter: a member of the SGLT family.
        J Biol Chem. 1992; 267: 3557-3560
        • Bawdon RE
        • Sobhi S
        • Dax J
        The transfer of anti-human immunodeficiency virus nucleoside compounds by the term human placenta.
        AM J OBSTET GYNECOL. 1992; 167: 1570-1574
        • Bawdon RE
        • Kaul S
        • Sobhi S.
        The ex vivo transfer of the anti-HIV nucleoside compound d4T in the human placenta.
        Gynecol Obstet Invest. 1994; 38: 1-4
        • Novy MJ
        • Thomas CL
        • Lees MH
        Uterine contractility and regional blood flow responses to oxytocin and prostaglandin E2 in pregnant rhesus monkeys.
        AM J OBSTET GYNECOL. 1975; 122: 419-433
        • Giroux M
        • Campistron G
        • Faure F
        • et al.
        Effects of pH on antipyrine transfer across the human placenta ex vivo.
        Dev Pharmacol Ther. 1990; 14: 153-160
        • Hirsch HA
        • Dreher E
        • Perrochet A
        • Schmid E.
        Transfer of ampicillin to the fetus and amniotic fluid during continuous infusion (steady-state) and by repeated single intravenous injections to the mother.
        Infection. 1974; 2: 207-212
        • Tuntland T
        • Odinecs A
        • Pereira C
        • Nosbisch C
        • Unadkat JD.
        In vitro-in vivo correlation of the mechanism and rate of placental transfer of anti-HIV dideoxynucleoside drugs.
        Pharm Res. 1995; 12 ([Abstract]): S4