Pharmacokinetics of azidothymidine during late pregnancy in Long-Evans rats

Little, Bertis B.; Bawdon, Roger E.; Christmas, James T.; Sobhi, Sohrab; Gilstrap, Larry C.

doi:10.1016/0002-9378(89)90391-8

Cited by 21 publications

(13 citation statements)

References 6 publications

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“…Animal studies have also shown rapid placental transfer of zidovudine, 12 and zidovudine has been shown to cross the placenta in explanted human placental cotyledon studies. 13,14 The drug may disrupt early embryonic development because, as mentioned previously, the mechanism of action of zidovudine is the inhibition of DNA replication.…”

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confidence: 98%

“…19 The absorption of zidovudine through intragastric intubation was documented in a prior investigation conducted in this laboratory in which the placental transfer was analyzed. 12 The greatest number of anatomic structures form in the rat embryo in the period of gestation from days [6][7][8][9][10][11] (taking insemination as day 0). By day 11, the neural structures have formed, somite development has occurred, and major organs (including heart, kidney, gastrointestinal tract, thyroid gland, and thymus) and limb buds have developed.…”

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confidence: 99%

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Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague‐Dawley Rats

Christmas

Little

Knoll

et al. 1994

Infectious Diseases in Obstetrics and Gynecology

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Objective: The purpose of the present investigation was to analyze the effets of zidovudine on the postimplantation embryo and fetus.Methods: Pregnant Sprague-Dawley rats were given various doses (10 mg/kg, 30 mg/kg, 150 mg/kg) of zidovudine or saline by an endotracheal tube during the period of embryogenesis (days 6-8, 9-11, 6-11 postconception). The animals were sacrificed on days 18-19 of pregnancy, and their fetuses were removed by hysterotomy. Autopsies under low (15) and high (40) power light microscopy were performed on all fetuses.Results: There was no statistically significant difference among the groups with respect to maternal weight gain. There were more pregnancy resorptions in the group receiving high-dose zidovudine (150 mg/kg/day) throughout embryogenesis than in the control group (P 0.001, respectively). Four major structural anomalies were noted among the 689 fetuses examined, but zidovudine was not associated with an increased frequency of congenital anomalies in rats when it was administered in doses similar to, 3-, and 15-fold higher than the regimen recommended for adult humans. The drug, however, was embryocidal in the high-dose group (P 0.002).Conclusions: These findings are consistent with previous studies of preimplantation mouse em-bryos that demonstrated an embryocidal effect on preimplantation conceptuses. In summary, postimplantation embryonic zidovudine exposure was associated with significantly increased pregnancy losses (resorptions and intrauterine deaths). (C) 1995 Wiley-Liss, Inc.

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confidence: 98%

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confidence: 99%

Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague‐Dawley Rats

Christmas

Little

Knoll

et al. 1994

Infectious Diseases in Obstetrics and Gynecology

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“…Unlike ACV, AZT is approved by the Food and Drug Administration for use during pregnancy. To date, several groups have investigated the placental transfer of AZT monotherapy by using animal or in vitro models (20,22,26,30,38). Huang et al developed a compartmental pharmacokinetic model for the pregnant rat that described AZT distribution in all matrices associated with pregnancy (maternal plasma, amniotic fluid, placenta, and fetal tissue) (26).…”

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confidence: 99%

Pharmacokinetics of Intravenous Acyclovir, Zidovudine, and Acyclovir-Zidovudine in Pregnant Rats

Brown

Bartlett

White

2003

Antimicrob Agents Chemother

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The pharmacokinetics and placental transfer of acyclovir and zidovudine monotherapies and acyclovirzidovudine combination therapy were compared in the pregnant rat. Timed-pregnancy Sprague-Dawley rats were used for the study. Doses of 60 mg of each drug/kg of body weight in monotherapy and in combination therapy were given by intravenous bolus, and samples of maternal plasma, amniotic fluid, fetal tissue, and placental tissue were collected over a period of 8 h postdose. Concentrations of each drug in the various matrices were measured by high-performance liquid chromatography. All data were analyzed by using WinNonlin. A one-compartment model with first-order elimination was used to fit the AZT plasma data from the combination therapy rats, but the plasma data from the other groups were fit to a two-compartment model. Tissue data were analyzed by noncompartmental analysis to generate area-under-the-concentration-time-curve values. Implementation of the combination therapy altered the pharmacokinetics of each drug compared to its monotherapy pharmacokinetics. The combination of these two drugs may potentiate fetal and amniotic fluid exposures to each drug., an acyclic analog of the natural nucleoside 2Ј-deoxyguanosine ( Fig. 1), is active against the members of the herpes group of DNA viruses (14, 42). For over 2 decades, ACV has been considered the first choice of treatment for herpes simplex virus types 1 and 2 (HSV-1 and -2), but it has also been shown to effectively treat varicella-zoster virus and provide protection from cytomegalovirus in immunosuppressed patients receiving transplants (12, 32). The success of ACV in treating HSV has prompted the synthesis of several structural analogs, but none has shown to be as tolerable as and have shown to have such a high therapeutic index as ACV (13,35,40). Zidovudine (3Ј-azido-3Ј-deoxythymidine [AZT]) (Fig. 1) is the premier reverse transcriptase inhibitor released for the treatment of human immunodeficiency virus (HIV). A therapy involving the combination of ACV and AZT is not uncommon to help suppress symptoms in patients who are both HIV positive and HSV-2 positive. These drugs, both in monotherapy and in combination, have been used to prevent vertical (mother-to-child) transmission of HSV-2 and HIV.The Acyclovir in Pregnancy Registry has compiled a large amount of case study information regarding the relative safety and efficacy of ACV use in HSV-2-positive pregnant women (1). Although a great deal is known about the pharmacokinetic properties of ACV, little work has been done to characterize the placental transfer of ACV in vivo, because pregnant women are routinely excluded from clinical trials. Pharmacokinetic parameters may be altered during pregnancy due to the increase in body fat content, cardiac output, and total body water seen in pregnant women (15,41,48). There may also be changes in plasma albumin concentration and protein binding affinities (25,39). The perfused human placenta model has been used on occasion in attempts to characterize the placenta...

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“…All earlier researchers chose initiation of antiviral therapy from day 10 of gestation [Little et al, 1989;Venerosi et al, 2001;Olivero et al, 2002], because early embryonic development is very important. By day 10 of the embryonic development, development of major systems, such as the nervous system, is completed, and hence the toxic effects of drugs on the fetus are reduced.…”

Section: Discussionmentioning

confidence: 99%

Preliminary study on the efficacy and safety of lamivudine and interferon α therapy in decreasing serum HBV DNA level in HBV positive transgenic mice during pregnancy

Duan

Choi

et al. 2005

Journal of Medical Virology

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Previous studies reported that the HBV DNA level in maternal serum is an important risk factor for intrauterine infection. Two antiviral drugs, lamivudine (3TC) and interferon alpha (IFNalpha), are used extensively clinically to reduce maternal HBV DNA level, However, because of a lack of evidence on the efficacy and safety of these drugs during pregnancy, they are categorized as grade C which prevents their use during pregnancy. This study provides new data on the efficacy and safety of lamivudine and IFNalpha in HBV positive transgenic pregnant mice. In this study, transgenic mice with high titers of hepatitis B virus (HBV) were employed to study the antiviral effects of 3TC and IFNalpha during different gestation periods. The study also examined changes in several serological HBV markers, the effects of perinatal exposure to antiviral drugs on the mother and offspring, drug efficacy in reducing the level of HBV DNA in maternal blood, and the safety to both the mother and offspring. The main conclusion of the study is that a significant decrease in HBV DNA level can be obtained after treatment with lamivudine but not with IFNalpha. No adverse effects were observed in the maternal mice and the offsprings. This finding may provide a rationale for the potential use of lamivudine for the treatment of pregnant women as a safe and effective measure to reduce the level of maternal viremia.

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Pharmacokinetics of azidothymidine during late pregnancy in Long-Evans rats

Cited by 21 publications

References 6 publications

Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague‐Dawley Rats

Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague‐Dawley Rats

Pharmacokinetics of Intravenous Acyclovir, Zidovudine, and Acyclovir-Zidovudine in Pregnant Rats

Preliminary study on the efficacy and safety of lamivudine and interferon α therapy in decreasing serum HBV DNA level in HBV positive transgenic mice during pregnancy

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