Maternal-Fetal Pharmacokinetics of Zidovudine in Rats

Huang, Christine; Boudinot, F. Douglas; Feldman, Stuart

doi:10.1021/js9505206

Cited by 14 publications

(12 citation statements)

References 35 publications

(60 reference statements)

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“…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). The consensus concerning AZT behavior in pregnancy is that it readily crosses the placenta via passive diffusion (20,22,26,38).…”

Section: Acyclovir (9-[{2-hydroxyethoxy}-methyl]-guanosine [Acv])mentioning

confidence: 99%

“…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). The consensus concerning AZT behavior in pregnancy is that it readily crosses the placenta via passive diffusion (20,22,26,38).The pregnant rat model has been used successfully in the study of the placental transfer of many compounds, including nucleoside analogs (2-4, 9, 11, 18, 23, 26-28, 36, 37, 46). The hemodynamic changes present in the pregnant rat are similar to those seen in a human pregnancy (3,16).…”

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confidence: 99%

“…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%

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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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Section: Acyclovir (9-[{2-hydroxyethoxy}-methyl]-guanosine [Acv])mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

Brown

Bartlett

White

2003

Antimicrob Agents Chemother

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“…Animal models present a good alternative to characterize the distribution of drugs across the placenta. Huang et al [19] reported a compartmental PK model for maternal-fetal transport of the anti-HIV drug zidovudine in rats. The authors evaluated three distributional models for maternal plasma, placenta, fetus, amniotic fluid and maternal tissue compartments.…”

Section: Modeling Drug Distributionmentioning

confidence: 99%

Recent advances in pharmacokinetic modeling

Ahmad

2007

Biopharm & Drug Disp

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A major part of the science of pharmacokinetics is the modeling of the underlying processes that contribute to drug disposition. The purpose of pharmacokinetic models is to summarize the knowledge gained in preclinical and clinical studies at various stages in drug development and to rationally guide future studies with the use of adequately predictive models. This review highlights a variety of recent advances in mechanistic pharmacokinetic modeling. It is aimed at a broad audience, and hence, an attempt was made to maintain a balance between technical information and practical applications of pharmacokinetic modeling. It is hoped that drug researchers from all disciplines would be able to get a flavor of the function and capacity of pharmacokinetic modelers and their contribution to drug development. While this review is not intended to be a technical reference on modeling approaches, the roles of statistical applications and population methodologies are discussed where appropriate.

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“…Therefore, an animal model must be utilized that will provide clinically useful mechanistic information. A pregnant rat model has been developed and used for the investigation of the basic mechanisms involved in the placental transfer of nucleoside analogs (Huang et al, 1996;Brown et al, 2003). The rat model has proved to be useful due to the similarities of the hemochorial placenta and hemodynamic pregnancy changes experienced in both rats and humans (Faber et al, 1983;Boike et al, 1989a).…”

Section: Introductionmentioning

confidence: 99%

Determination of didanosine in maternal plasma, amniotic fluid, fetal and placental tissues by high‐performance liquid chromatography–tandem mass spectrometry

Clark

White

Bartlett

2006

Biomedical Chromatography

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A rapid and efficient high-performance liquid chromatography (HPLC)-tandem mass spectrometry method for the determination of didanosine concentrations in maternal rat plasma, amniotic fluid, placental and fetal tissue samples has been developed and validated. Tissue samples were homogenized in optima water and centrifuged. The supernatant was subjected to solid-phase extraction (SPE) prior to analysis. Plasma and amniotic fluid samples were extracted without pretreatment. An Agilent 1100 Series HPLC coupled with a Micromass Quattro II triple quadrupole mass spectrometer was used for all analyses. Chromatographic resolution was achieved on a Nova-Pak phenyl analytical column (2.0 x 150 mm, 4 microm particle size) equipped with a Phenomenex Security-guard phenyl guard cartridge (2.0 x 4.0 mm) using 60% methanol in 10 mm ammonium acetate buffer mobile phase for all matrices at a flow rate of 0.15 mL/min. The method yields retention times of 2.9 min for didanosine and 3.0 min for the internal standard, stavudine. Limits of detection were 1 ng/mL for all matrices. Recoveries were 70% or greater for both compounds in the different matrices. Within- and between-run precision (%RSD) and accuracy (%error) was less than 15% for all matrices.

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Maternal-Fetal Pharmacokinetics of Zidovudine in Rats

Cited by 14 publications

References 35 publications

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

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

Recent advances in pharmacokinetic modeling

Determination of didanosine in maternal plasma, amniotic fluid, fetal and placental tissues by high‐performance liquid chromatography–tandem mass spectrometry

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