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 t1/2 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 mumol/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 2 hr 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 mumol/kg. The t1/2 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 mumol/kg suggests either long-term down-regulation of the expression of ADA or irreversible damage to ADA-containing neurons.
D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001921:Brain / Q000201:enzymology; D003070:Coformycin / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D007421:Intestine, Small / Q000201:enzymology; D008297:Male; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D015649:Pentostatin; D051381:Rats; D011919:Rats, Inbred Strains; D012263:Ribonucleosides / Q000493:pharmacokinetics*
D058892:Adenosine Deaminase Inhibitors; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase