Disposition and metabolism in mice of the potential antitumor and anti-human immunodeficiency virus-1 agent, 2-chloro-2',3'-dideoxyadenosine.
A high-performance liquid chromatographic (HPLC) procedure was developed to examine the preclinical pharmacology and pharmacokinetics of 2-chloro-2',3'-dideoxyadenosine (ClddAd). The HPLC assay for ClddAd in human plasma was linear from 0.25 to 500 micrograms ClddAd/ml. Coefficients of variation for the measurement of ClddAd in human plasma were 9.7%, 4.1%, and 2.7% at 2.5, 25, and 250 micrograms/ml, respectively. Binding of ClddAd to human and mouse plasma proteins was determined by filtration to be 26.9% and 34.4%, respectively. ClddAd concentrations decreased by less than 5% when ClddAd was stored for 126 h at 37 degrees C in 0.9% NaCl or 0.1 M NaH2PO4 (pH 7.4) or when ClddAd was stored for 24 h at 37 degrees C in citrate-buffered human blood or plasma. Estimates of the lethal dose for 50% (LD50) and 10% (LD10) of male CD2F1 mice that received a single i.v. dose of ClddAd were 27 and 24 mg/kg, respectively. Elimination of a 24-mg/kg i.v. bolus dose of ClddAd from mouse plasma was biphasic, with half-lives of 0.73 and 14.7 min. The apparent volume of distribution of ClddAd was 215 ml/kg and the total body clearance was 20 ml min-1 kg-1. No ClddAd metabolites were detected in mouse plasma after in vivo exposure or in human whole blood or plasma after in vitro incubation. ClddAd was detected in the urine of mice within 2 min after exposure, and the total urinary excretion of unchanged ClddAd for 24 h after exposure to 24 mg/kg was 3.4% of the delivered dose. At least two possible ClddAd metabolites were detected in mouse urine; they did not co-elute with 2-chloro-2',3'-dideoxyinosine,2-chloradenine, or 2-chlorohypoxanthine.
Chapman
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Department of Pharmacology, Mayo Clinic & Foundation, Rochester, MN 55905.
Powis
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D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003641:Deamination; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects*; D006207:Half-Life; D008297:Male; D051379:Mice; D011485:Protein Binding
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001798:Blood Proteins; C055504:2-chloro-2',3'-dideoxyadenosine; D016048:Dideoxyadenosine