Pharmacokinetics of 2′-deoxycoformycin, an inhibitor of adenosine deaminase, in the rat

The distribution of the potent inhibitor of adenosine deaminase (ADA), 2′-deoxycoformycin (DCF), in the brain of the rat and its inhibition of ADA in brain and gut was determined. The accumulation of [³H]DCF in brain was maximal 2 hr after intraperitoneal injection and elimination was best described by a two compartment model having t _{1 2} phases of about 1-5 hr and 50 hr. The activity of ADA in gut exhibited dose-related inhibition at 1.9, 3.7 and 18.6 μmol/kg (i.p.) and returned to normal by 16 days. In brain, ADA was inhibited by about 95% at all three of these doses of DCF 2hr after injection and activity returned to control levels by 30 days with the two smaller doses, but remained at 66% of control levels at 50 days with 18.6 μmol/kg. The t _{1 2} of the recovery of the activity of ADA in both brain and gut was found to be dose-dependent. The failure of the activity of ADA in brain to recover after treatment with 18.6 μmol/kg suggests either long-term down-regulation of the expression of ADA or irreversible damage to ADA-containing neurons.