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, h as been tested in phase II trials in the treatment of lymphoproliferat ive disorders, 2-Chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA). a n acid stable derivative of CdA with promising anti-lymphoproliferativ e activity, has been suggested as a potentially effective oral drug. I n the present study, we investigated the metabolism of CdA and CAFdA i n isolated perfused rat liver. The liver was recycled with a perfusate containing CdA or CAFdA (2-200 mu g/ml) for 3.5 h. The elimination ha lf-lives were concentration-dependent for both CdA and CAFdA. The elim ination rate of CAFdA was slower than that of CdA, suggesting that CAF dA 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 exp eriment and less than 1% of CdA and 0.1% of CAFdA were found as CAde i n the bile, respectively. The structural identity of metabolites prese nt in the perfusates was verified utilizing electrospray ionization ma ss spectrometry.