Transplacental pharmacokinetics and fetal distribution of 2?,3?-didehydro-3?-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques

Patterson, Tucker A.; Binienda, Zbigniew; Newport, Glenn D.; Lipe, George W.; Gillam, Michael; Slikker, William; Sandberg, Jennifer A.

doi:10.1002/1096-9926(200008)62:2<93::aid-tera5>3.0.co;2-m

Cited by 19 publications

(7 citation statements)

References 19 publications

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“…Similarly, infant patas monkeys born to dams given humanequivalent NRTI dosing during gestation showed a large inter-individualindividual variability in AZT-DNA incorporation in many different organs taken at birth (Olivero et al, 2002). Given that AZT pharmacokinetics and metabolism are similar in all primates studied (Moodley et al, 1998;O'Sullivan et al, 1993;Patterson et al, 1997;Divi et al, 2007), the observed variability in AZT-DNA levels presented a curious finding. Perhaps the current study at least partially explains the previously-observed AZT-DNA variability as being caused by interindividualindividual differences in TK1 inducibility in the presence of AZT.…”

Section: Discussionmentioning

confidence: 98%

Human inter-individual variability in metabolism and genotoxic response to zidovudine

Olivero

Ming

Das

et al. 2007

Toxicology and Applied Pharmacology

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A mainstay of the antiretroviral drugs used for therapy of HIV-1, zidovudine (AZT) is genotoxic and becomes incorporated into DNA. Here we explored host inter-individual variability in AZT-DNA incorporation, by AZT radioimmunoassay (RIA), using 19 different strains of normal human mammary epithelial cells (NHMECs) exposed for 24 h to 200 microM AZT. Twelve of the 19 NHMEC strains showed detectable AZT-DNA incorporation levels (16 to 259 molecules of AZT/10(6) nucleotides), while 7 NHMEC strains did not show detectable AZT-DNA incorporation. In order to explore the basis for this variability, we compared the 2 NHMEC strains that showed the highest levels of AZT-DNA incorporation (H1 and H2) with 2 strains showing no detectable AZT-DNA incorporation (L1 and L2). All 4 strains had similar (> or =80%) cell survival, low levels of accumulation of cells in S-phase, and no relevant differences in response to the direct-acting mutagen bleomycin (BLM). Finally, when levels of thymidine kinase 1 (TK1), the first enzyme in the pathway for incorporation of AZT into DNA, were determined by Western blot analysis in all 19 NHMEC strains at 24 h of AZT exposure, higher TK1 protein levels were found in the 12 strains showing AZT-DNA incorporation, compared to the 7 showing no incorporation (p=0.0005, Mann-Whitney test). Furthermore, strains L1 and L2, which did not show AZT-DNA incorporation at 24 h, did have measurable incorporation by 48 and 72 h. These data suggest that variability in AZT-DNA incorporation may be modulated by inter-individual differences in the rate of induction of TK1 in response to AZT exposure.

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Section: Discussionmentioning

confidence: 98%

Human inter-individual variability in metabolism and genotoxic response to zidovudine

Olivero

Ming

Das

et al. 2007

Toxicology and Applied Pharmacology

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“…Extensive placental passage is primarily due to their relatively high volume of distribution, low molecular weights and limited plasma protein binding. Moreover, numerous animal [10], in vitro [11] and ex vivo [12][13][14][15] models of the human placenta support the high placental accumulation of these agents.…”

Section: Nucleoside/nucleotide Reverse Transcriptase Inhibitorsmentioning

confidence: 98%

Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Fetal Compartment (Placenta and Amniotic Fluid)

et al. 2011

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HIV resides within anatomical 'sanctuary sites' where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect. Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivo pharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy.

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“…In the patas, we have measured AZT/ 3TC pharmacokinetics in adult, nonpregnant animals but not in pregnant dams. However, the uniformity in NRTI metabolism, and similarity in gestational pharmacodynamics among all the primate species studied (Patterson et al, 1997) suggests that the pregnant patas will process NRTIs in a fashion very similar to pregnant women and the other primate counterparts.…”

Section: Perinatal Nrti Exposure Induces Brain and Liver Mitochondriamentioning

confidence: 99%

Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Divi

Einem

Fletcher

et al. 2010

Toxicological Sciences

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Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8-51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function.

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Transplacental pharmacokinetics and fetal distribution of 2?,3?-didehydro-3?-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques

Cited by 19 publications

References 19 publications

Human inter-individual variability in metabolism and genotoxic response to zidovudine

Human inter-individual variability in metabolism and genotoxic response to zidovudine

Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Fetal Compartment (Placenta and Amniotic Fluid)

Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

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