Abstract
The technique of accelerator mass spectrometry (AMS) was validated successfully and used to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (7-deaza-2'-C-methyl-adenosine; Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across subpharmacological (microdose) and pharmacological dose ranges in an animal model, before initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as liquid chromatography-tandem mass spectrometry and liquid scintillation counting analyses. Compound A displayed multiphasic kinetics and exhibited low plasma clearance (5.8 ml/min/kg), a long terminal elimination half-life (17.5 h), and high oral bioavailability (103%). Currently, there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus subpharmacological doses using microdosing strategies. The present study thus provides the first description of the full pharmacokinetic profile of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A following dosing at 0.02 mg/kg were similar to those at 1 mg/kg, indicating that in the case of Compound A, the pharmacokinetics in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even after a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques.
Footnotes
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This work was performed in part at the Research Resource for Biomedical AMS which is operated at Lawrence Livermore National Laboratory under the auspices of the U.S. Department of Energy under Contract W-7405-Eng-48. The Research Resource is supported by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program Grant P41 RR13461.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.000422.
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ABBREVIATIONS: AMS, accelerator mass spectrometry; AUC, area under the plasma concentrations versus time curve; Compound A, 7-deaza-2'-C-methyl-adenosine; Cmax, maximum concentration in plasma; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LSC, liquid scintillation counting; Tmax, time of occurrence of maximum concentration in plasma; Vdss, steady-state volume of distribution.
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↵1 Current address: Department of Pharmacokinetics and Drug Metabolism, Amgen Biologicals, Thousand Oaks, CA 91320.
- Received May 6, 2004.
- Accepted July 30, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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