Aspects of the purine nucleoside phosphorylase (PNP) deficient state produced in normal rats following oral administration of 8-amino-9-(2-thienylmethyl)guanine (PD 119,229), a novel inhibitor of PNP

Abstract

8-Amino-9-(2-thienylmethyl)guanine (PD 119,229; 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purine-6-one monohydrochloride) is a potent inhibitor of human purine nucleoside phosphorylase (PNP). The effects of orally administered PD 119,229 on the plasma concentration of the PNP substrates, inosine and guanosine, were determined using normal rats. In time course studies following administration of a single 3 mg/kg dose of PD 119,229, both inosine and guanosine were statistically significantly elevated as soon as one hr postdose. Plasma inosine elevation was maximal ten hr after dosing, reaching a mean of 2.13 μM (14.2-fold vehicle). Guanosine was maximally elevated at three hr following a single 3 mg/kg oral dose, reaching a mean of 0.77 μM (4.5-fold vehicle). In dose-response studies in which blood specimens were obtained one hr following oral administration of PD 119,229 at doses of 1.5 to 50 mg/kg, maximal mean inosine elevation (1.71 μM or 57-fold vehicle) occurred at 15 mg/kg, with a plateauing or decline in inosine concentration noted at higher doses. The maximal mean plasma guanosine concentration was achieved at 50 mg/kg (mean of 0.2 μM, or 6.7-fold vehicle). Substantially greater nucleoside elevation was not observed following multiple oral 15 mg/kg doses, nor when nucleoside levels were assessed at two to four hr following a large oral dose. However, inosine levels reaching 15 μM, and guanosine concentrations approaching 2 μM, were occasionally noted in individual rats. It is concluded that oral administration of PD 119,229 can simulate, in normal rats, one of the more readily detectable biochemical abnormalities of the PNP deficient state in humans.