PD-141955 AND CI-972 - 9-DEAZAGUANINE ANALOG PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITORS .2. EFFECTS ON NUCLEOSIDE CATABOLISM IN HUMAN AND RAT-BLOOD IN-VITRO
Mk. Dong et Rb. Gilbertsen, PD-141955 AND CI-972 - 9-DEAZAGUANINE ANALOG PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITORS .2. EFFECTS ON NUCLEOSIDE CATABOLISM IN HUMAN AND RAT-BLOOD IN-VITRO, Agents and actions, 39, 1993, pp. 30000099-30000101
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 b
ecause it serves as a precursor of dGTP, which blocks T-cell replicati
on, thus leading to T-cell-selective immune dysfunction. We adapted th
ese 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 14
1955 (9-deaza-943-thienylmethyl)guanine; 3-thienylmethyl)-4H-pyrrolo[3
,2-d]pyrimidin-4-one) and CI-972 (8-amino-9-deaza-9-(3-thienylmethyl)g
uanine; 3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one) on GdR cata
bolism were determined. GdR was metabolized 89 times faster in human b
lood than in rat blood (half-life = 12.0 +/- 1.4 s in human blood). Wh
en PD 141955 (1 mug/ml) was added to human blood before spiking, the G
dR half-life increased to > 60 min. In contrast, CI-972 (1 mug/ml) ext
ended 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.