Pharmacokinetics of the anticancer agent 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine in rats.
The pharmacokinetics of a new 2-halo-2'-deoxyadenosine analogue, 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine [CL-F-ara-A], was characterized in rats following the development of a new high-performance liquid chromatography (HPLC) technique. This halogenated derivative was thought to have improved gastrointestinal stability that would facilitate oral administration. The HPLC method consisted of a single ethyl acetate extraction and reverse-phase chromatographic conditions. The method resulted in approximately 83% recovery of CL-F-ara-A from plasma and a sensitivity of 20 ng/ml. At i.v. doses of 10 and 25 mg/kg, the total clearance of CL-F-ara-A decreased from 2.1 to 1.5 l h-1 kg-1, with the reduction being attributed to saturation of metabolism. The elimination half-lives following i.v. bolus administrations were estimated to be a mean of 1.35 and 1.84 h at the two respective doses. The volume of distribution at steady state was not significantly different at the two doses, being 3.6 and 3.2 l/kg. The percentage of protein binding of CL-F-ara-A in rat plasma was only 13.3%. Administration of equivalent oral doses resulted in bioavailability estimates of approximately 50%, indicating that oral treatment regimens of CL-F-ara-A are feasible.
Qian
M
M
Department of Pharmaceuties, College of Pharmacy, University of Georgia, Athens.
Wang
X
X
Shanmuganathan
K
K
Chu
C K
CK
Gallo
J M
JM
D000227:Adenine Nucleotides; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D000077866:Clofarabine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D000077866:Clofarabine