Excretion patterns of 125I-radioiodohippuric acid in normal and in chronically uremic rats

Tse, J.W.; Shysh, A.; Wiebe, Leonard I.

doi:10.1016/0047-0740(78)90030-x

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…of these compounds. It is surprising that Iipophilicity (range log P of 0.04-»1.1) and molecular weight (range 367-549 daltons) had little influence on the hepatobiliary uptake and clearance of these compounds, since both properties are generally accepted as predictors of hepatobiliary clearance (Tse et al, 1978). These prod rugs have only low protein binding (in the range of 10-20% compared to 7% for EDU, by bovine serum albumin), so it is unlikely that any substantial effect could be attributed to this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

Cheraghali

Kumar

Morin

et al. 1995

Antivir Chem Chemother

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(+)- Trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5′-O-valeryl-2′-deoxyuridine (3) and (+)- trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-3′,5′-di-O-valery[-2′-deoxyuridine (4) were synthesized in 55% and 8.6% yield, respectively, by esterification of the 5′-hydroxyl group of (+)- trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-2′-deoxyuridine (2) using valeryl chloride. [4-14C]-3 and [4-14C]-4 were synthesized in 79% and 64% chemical and radiochemical yield, respectively, by similar esterifications of [4-14C]-2. The double prodrug 3 was readily hydrolysed (> 95% in 8 min) to 5-ethyl-2′-deoxyuridine (EDU) by porcine liver esterase in vitro. The biotransformations of 2 and 3 were studied following i.v. injection of a 0.4 mmol/kg i.v. dose to male Balb/c mice. The single prodrug 2 was rapidly cleared (<10 min) from the blood. The area under the blood concentration-time curve (AUC) for EDU, as a metabolite of 2, was higher (2.1 ± 0.4 μmol.h.g−1) than the AUC observed when EDU itself was injected (1.7 ± 0.2 μmol.h.g−1). The double prodrug 3 provided a sustained high concentration of EDU in blood, with an AUC for EDU, as a metabolite of 3, of 1.8 ± 0.2 μmol.hr.g−1. 5′-O-Valeryl-5-ethyl-2′-deoxyuridine and 3 were both detected in blood samples collected up to 35 min post i.v. injection. 5-Ethyluracil and 5-(1-hydroxyethyl)-uracil were identified as secondary metabolites of EDU, 2 and 3. Compared to [4-14C]-EDU, i.v. injection of [4-14C]-3 or [4-14C]-4 provided significantly higher (P < 0.001) radioactivity levels in the brain, but neither EDU, 2 or 3 protected mice against intracerebral herpes simplex virus infection. Hepatic uptakes of 2, 3 and 4, in mice, were similar to each other despite the respective substantial increases in both molecular weight and lipophilicity of this series. In rats, biliary excretion over the 0-4 h period after i.v. injection accounted for only 2.9-3.9% of the injected dose for these prodrugs.

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Section: Discussionmentioning

confidence: 99%

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

Cheraghali

Kumar

Morin

et al. 1995

Antivir Chem Chemother

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Hepatic reticuloendothelial function in the sub-totally nephrectomized rat model of chronic uremia

1979

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The chronic uremic condition was induced in male Wistar rats by long term maintenance of the animals following sequential sub-total and contralateral nephrectomies. Hepatic reticuloendothelial (RES) activity was estimated by non-invasive measurement of blood clearance rates and hepatic uptake of 99Tcm sulfur colloid administered intravenously. The blood half-time, and the blood clearance rate constants for normals and chronic uremics were 78 +/- 10 s and 49.5 +/- 5 s, and 7.51 +/- 1.04 x 10(-3) s-1 and 10.81 +/- 1.17 x 10(-3) s-1 respectively. The normal hepatic uptake rate constant was 9.03 +/- 1.25 x 10(-3) s-1, compared with a uremic uptake rate constant of 14.34 +/- 1.51 s-1. Measurement of total liver radioactivity upon termination, 15 min after injection, showed significantly increased total uptake in uremia, whereas no change in spleen radioactivity was observed. The clinical implications of these data are discussed.

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Bone fluoride in chronically uremic rats

Wiebe

Shysh

Apps

et al. 1983

J. Radioanal. Chem.

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Excretion patterns of 125I-radioiodohippuric acid in normal and in chronically uremic rats

Cited by 3 publications

References 7 publications

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

Hepatic reticuloendothelial function in the sub-totally nephrectomized rat model of chronic uremia

Bone fluoride in chronically uremic rats

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