title: PD 141955 and CI-972: 9-deazaguanine analog purine nucleoside phosphorylase inhibitors. II. Effects on nucleoside catabolism in human and rat blood in vitro.
abstract: 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.
authors.affiliation: Department of Immunopathology, Parke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48105.
authors.forename: M K
authors.initials: MK
authors.lastname: Dong
authors.forename: R B
authors.initials: RB
authors.lastname: Gilbertsen
mesh_terms: 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*
chemical_list: 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