Clinical pharmacology of 9-beta-D-arabinofuranosyladenine in combination with 2'-deoxycoformycin.
It has been suggested that, by inhibiting the adenosine deaminase (ADA)-mediated catabolism of 9-beta-D-arabinofuranosyladenine (ara-A), 2'-deoxycoformycin (DCF) would increase the half-life (t1/2) of ara-A, a compound with known antileukemic activity. To test this hypothesis, we collected serial plasma samples from five patients with refractory acute lymphoblastic leukemia who participated in a Phase I trial of i.v. DCF 915 mg/sq m) in combination with i.v. single-dose ara-A (120-250 mg/sq m). In four of these patients, of whom three were known to have achieved greater than 98% ADA inhibition, a mean ara-A t1/2 of 227 min was achieved. Extrapolated peak levels (i.e., following infusion of ara-A) ranged from 1.5 to 7.4 micrograms/ml (mean, 4.2 micrograms/ml). Elimination of drug appeared to follow a single-compartment model. In two patients who received ara-A without prior DCF and in a third patient who had significant residual ADA activity despite DCF, ara-A was unmeasurable within 5 min of the end of infusion. These data confirm that the kinetics of ara-A catabolism can be altered by inhibition of ADA and suggest that more than one dose of DCF may be necessary for complete inhibition of the enzyme and optimal pharmacological modulation of ara-A.
D000293:Adolescent; D000328:Adult; D001087:Arabinonucleosides / Q000378:metabolism; D002675:Child, Preschool; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D007042:Hypoxanthines / Q000378:metabolism; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D015649:Pentostatin; D012263:Ribonucleosides / Q000494:pharmacology*; D014740:Vidarabine / Q000378:metabolism* / Q000627:therapeutic use
D001087:Arabinonucleosides; D007042:Hypoxanthines; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; C008099:hypoxanthine arabinoside; D014740:Vidarabine