Kinetics and metabolism of 2-chloro-2'-deoxyadenosine and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine in the isolated perfused rat liver.
2-Chloro-2'-deoxyadenosine (CdA), a newly developed anticancer drug, has been tested in phase II trials in the treatment of lymphoproliferative disorders. 2-Chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA), an acid stable derivative of CdA with promising anti-lymphoproliferative activity, has been suggested as a potentially effective oral drug. In the present study, we investigated the metabolism of CdA and CAFdA in isolated perfused rat liver. The liver was recycled with a perfusate containing CdA or CAFdA (2-200 micrograms/ml) for 3.5 h. The elimination half-lives were concentration-dependent for both CdA and CAFdA. The elimination rate of CAFdA was slower than that of CdA, suggesting that CAFdA is more stable than CdA against deglycosylation by hepatic enzymes. The amount of 2-chloroadenine (CAde), the major metabolite of CdA and CAFdA, increased proportionally with time and dose. The first passage effect was approximately 50% both for CdA and CAFdA. Less than 1% of CdA and CAFdA were recovered as intact drug in the bile during the experiment and less than 1% of CdA and 0.1% of CAFdA were found as CAde in the bile, respectively. The structural identity of metabolites present in the perfusates was verified utilizing electrospray ionization mass spectrometry.
Albertioni
F
F
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Hassan
M
M
Silberring
J
J
Liliemark
J
J
D000227:Adenine Nucleotides; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D001087:Arabinonucleosides / Q000097:blood / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D017338:Cladribine / Q000097:blood / Q000378:metabolism*; D000077866:Clofarabine; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D017338:Cladribine; D000077866:Clofarabine