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Title: Disposition of intravenous radioactive acyclovir

Abstract

The kinetic and metabolic disposition of (8-14C)acyclovir (ACV) was investigated in five subjects with advanced malignancy. The drug was administered by 1-hr intravenous infusion at doses of 0.5 and 2.5 mg/kg. Plasma and blood radioactivity-time, and plasma concentration-time data were defined by a two-compartment open kinetic model. There was nearly equivalent distribution of radioactivity in blood and plasma. The overall mean plasma half-life and total body clearance +/- SD of ACV were 2.1 +/- 0.5 hr and 297 +/- 53 ml/min/1.73 m2. Binding of ACV to plasma proteins was 15.4 +/- 4.4%. Most of the radioactive dose excreted was recovered in the urine (71% to 99%) with less than 2% excretion in the feces and only trace amounts in the expired Co2. Analyses by reverse-phase high-performance liquid chromatography indicated that 9-(carboxymethoxymethyl)guanine was the only significant urinary metabolite of ACV, accounting for 8.5% to 14.1% of the dose. A minor metabolite (less than 0.2% of dose) had the retention time of 8-hydroxy-9-((2-hydroxyethoxy)methyl)guanine. Unchanged urinary ACV ranged from 62% to 91% of the dose. There was no indication of ACV cleavage to guanine. Renal clearance of ACV was approximately three times the corresponding creatinine clearances.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Wellcome Research Laboratories, Research Triangle Park, NC
OSTI Identifier:
5511035
Resource Type:
Journal Article
Resource Relation:
Journal Name: Clin. Pharmacol. Ther.; (United States); Journal Volume: 30:5
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; 62 RADIOLOGY AND NUCLEAR MEDICINE; CARBON 14 COMPOUNDS; RADIONUCLIDE KINETICS; RADIOPHARMACEUTICALS; CLEARANCE; BIOLOGICAL LOCALIZATION; CARBON DIOXIDE; FECES; METABOLISM; METABOLITES; PATIENTS; RADIATION DOSES; URINE; BIOLOGICAL MATERIALS; BIOLOGICAL WASTES; BODY FLUIDS; CARBON COMPOUNDS; CARBON OXIDES; CHALCOGENIDES; DOSES; DRUGS; LABELLED COMPOUNDS; MATERIALS; OXIDES; OXYGEN COMPOUNDS; WASTES; 560171* - Radiation Effects- Nuclide Kinetics & Toxicology- Man- (-1987); 550601 - Medicine- Unsealed Radionuclides in Diagnostics

Citation Formats

de Miranda, P., Good, S.S., Laskin, O.L., Krasny, H.C., Connor, J.D., and Lietman, P.S.. Disposition of intravenous radioactive acyclovir. United States: N. p., 1981. Web. doi:10.1038/clpt.1981.218.
de Miranda, P., Good, S.S., Laskin, O.L., Krasny, H.C., Connor, J.D., & Lietman, P.S.. Disposition of intravenous radioactive acyclovir. United States. doi:10.1038/clpt.1981.218.
de Miranda, P., Good, S.S., Laskin, O.L., Krasny, H.C., Connor, J.D., and Lietman, P.S.. Sun . "Disposition of intravenous radioactive acyclovir". United States. doi:10.1038/clpt.1981.218.
@article{osti_5511035,
title = {Disposition of intravenous radioactive acyclovir},
author = {de Miranda, P. and Good, S.S. and Laskin, O.L. and Krasny, H.C. and Connor, J.D. and Lietman, P.S.},
abstractNote = {The kinetic and metabolic disposition of (8-14C)acyclovir (ACV) was investigated in five subjects with advanced malignancy. The drug was administered by 1-hr intravenous infusion at doses of 0.5 and 2.5 mg/kg. Plasma and blood radioactivity-time, and plasma concentration-time data were defined by a two-compartment open kinetic model. There was nearly equivalent distribution of radioactivity in blood and plasma. The overall mean plasma half-life and total body clearance +/- SD of ACV were 2.1 +/- 0.5 hr and 297 +/- 53 ml/min/1.73 m2. Binding of ACV to plasma proteins was 15.4 +/- 4.4%. Most of the radioactive dose excreted was recovered in the urine (71% to 99%) with less than 2% excretion in the feces and only trace amounts in the expired Co2. Analyses by reverse-phase high-performance liquid chromatography indicated that 9-(carboxymethoxymethyl)guanine was the only significant urinary metabolite of ACV, accounting for 8.5% to 14.1% of the dose. A minor metabolite (less than 0.2% of dose) had the retention time of 8-hydroxy-9-((2-hydroxyethoxy)methyl)guanine. Unchanged urinary ACV ranged from 62% to 91% of the dose. There was no indication of ACV cleavage to guanine. Renal clearance of ACV was approximately three times the corresponding creatinine clearances.},
doi = {10.1038/clpt.1981.218},
journal = {Clin. Pharmacol. Ther.; (United States)},
number = ,
volume = 30:5,
place = {United States},
year = {Sun Nov 01 00:00:00 EST 1981},
month = {Sun Nov 01 00:00:00 EST 1981}
}
  • The metabolic fate and the kinetics of elimination of (8-/sup 14/C)acyclovir in plasma and blood was investigated in five cancer patients. Doses of 0.5 and 2.5 mg/kg were administered by one-hour intravenous infusion. Radioactivity was distributed nearly equally in blood and plasma. The plasma and blood concentration-time data were defined by a two-compartment open pharmacokinetic model. The overall mean acyclovir plasma half-life and total body clearance +/- SD were 2.1 +/- 0.5 hours and 297 +/- 53 ml/min/1.73 m2. Binding of acyclovir to plasma proteins was 15.4 +/- 4.4 percent. The radioactive dose was excreted predominantly in the urine (71more » to 99 percent) with less than 2 percent excretion in the feces and only trace amounts of radioactivity in the expired air. Reverse-phase high-performance liquid chromatography indicated that 9-carboxymethoxymethylguanine was the only significant urinary metabolite of acyclovir accounting for 8.5 to 14.1 percent of the dose. A minor metabolite (less than 0.2 percent of dose) had the retention time of 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. Unchanged urinary acyclovir ranged from 62 to 91 percent of the dose. There was no indication of acyclovir cleavage to guanine. The renal clearances of acyclovir were three times higher than the corresponding creatinine clearances.« less
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  • Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP weremore » examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-{sup 13}C]1-BrP and [1-{sup 14}C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO{sub 2}, urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or {sup 14}CO{sub 2} (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ({approx} 50%) and high ({approx} 71%) dose groups; while the percentage of the dose exhaled as {sup 14}CO{sub 2} decreased (19 to 10%). The molar ratio of exhaled {sup 14}CO{sub 2} to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [{sup 14}C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (< 2%), or retained in the tissues and carcass (< 6%) of rats and mice administered i.v. 5 to 100 mg/kg [{sup 14}C]1-BrP. Metabolites characterized in urine of rats and mice include N-acetyl-S-propylcysteine, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-S-(2-hydroxypropyl)cysteine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl)cysteine, and N-acetyl-3-[(2-oxopropyl)sulfinyl]alanine. These metabolites may be formed following oxidation of 1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats pretreated with 1-aminobenzotriazole (ABT), a potent inhibitor of P450 excreted less in urine ({down_arrow}30%), exhaled as {sup 14}CO2 ({down_arrow}80%), or retained in liver ({down_arrow}90%), with a concomitant increase in radioactivity expired as VOC ({up_arrow}52%). Following ABT pretreatment, rat urinary metabolites were reduced in number from 10 to 1, N-acetyl-S-propylcysteine, which accounted for > 90% of the total urinary radioactivity in ABT pretreated rats. Together, these data demonstrate a role for cytochrome P450 and glutathione in the dose-dependent metabolism and disposition of 1-BrP in the rat.« less
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