PD-141955 AND CI-972 - 9-DEAZAGUANINE ANALOG PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITORS .2. EFFECTS ON NUCLEOSIDE CATABOLISM IN HUMAN AND RAT-BLOOD IN-VITRO

Patients with deficiency in purine nucleoside phosphorylase (PNP) have elevated levels of the PNP substrates inosine, guanosine, and (rarely) 2'-deoxyguanosine (GdR) in their plasma and urine. GdR is critical because it serves as a precursor of dGTP, which blocks T-cell replication, thus leading to T-cell-selective immune dysfunction. We adapted these findings to the study of PNP inhibitors in human and rat blood in vitro. Blood was spiked with GdR (2.5 mug/ml) and the effects of PD 141955 (9-deaza-943-thienylmethyl)guanine; 2-amino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one) and CI-972 (8-amino-9-deaza-9-(3-thienylmethyl)guanine; 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one) on GdR catabolism were determined. GdR was metabolized 89 times faster in human blood than in rat blood (half-life = 12.0 +/- 1.4 s in human blood). When PD 141955 (1 mug/ml) was added to human blood before spiking, the GdR half-life increased to > 60 min. In contrast, CI-972 (1 mug/ml) extended the GdR half-life to 7.2 +/- 1.7 min. Both PD 141955 and CI-972 at 1 mug/ml significantly retarded GdR catabolism from rat blood.