PD 141955 and CI-972: 9-deazaguanine analog purine nucleoside phosphorylase inhibitors. II. 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 micrograms/ml) and the effects of PD 141955 (9-deaza-9-(3-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]pyrim idin-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 microgram/ml) was added to human blood before spiking, the GdR half-life increased to > 60 min. In contrast, CI-972 (1 microgram/ml) extended the GdR half-life to 7.2 +/- 1.7 min. Both PD 141955 and CI-972 at 1 microgram/ml significantly retarded GdR catabolism from rat blood.
Dong
M K
MK
Department of Immunopathology, Parke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48105.
Gilbertsen
R B
RB
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003849:Deoxyguanosine / Q000097:blood* / Q000652:urine; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D011743:Pyrimidines; D013876:Thiophenes; C070377:CI 972; C076778:9-deaza-9-(3-thienylmethyl)guanine; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine