TY - JOUR T1 - EVALUATION OF MICRODOSING STRATEGIES FOR STUDIES IN PRECLINICAL DRUG DEVELOPMENT: DEMONSTRATION OF LINEAR PHARMACOKINETICS IN DOGS OF A NUCLEOSIDE ANALOG OVER A 50-FOLD DOSE RANGE JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1254 LP - 1259 DO - 10.1124/dmd.104.000422 VL - 32 IS - 11 AU - Punam Sandhu AU - John S. Vogel AU - Mark J. Rose AU - Esther A. Ubick AU - Janice E. Brunner AU - Michael A. Wallace AU - Jennifer K. Adelsberger AU - Maribeth P. Baker AU - Paul T. Henderson AU - Paul G. Pearson AU - Thomas A. Baillie Y1 - 2004/11/01 UR - http://dmd.aspetjournals.org/content/32/11/1254.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -