title: Blockade of nucleoside degradation in monkey whole blood in vitro by CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor.
abstract: Purine nucleosides HxR or GdR (2.5 micrograms/mL blood) were added to EDTA-treated cynomolgus monkey whole blood in vitro, alone or with the PNP inhibitor CI-1000 (1 microgram/mL), mixed, and the concentration of nucleosides remaining in plasma followed as a function of time. The half-lives of GdR and HxR in control blood were 1.2 and < 1 min, respectively, and were extended to 17.8 and 39.8 min, respectively, by coaddition of CI-1000. In contrast, a structural analog of CI-1000, CI-972, when tested in parallel at 1 microgram/mL, had markedly less effect on the breakdown of either nucleoside. The ability of CI-1000 to retard nucleoside breakdown in blood in vitro may be a predictor of in vivo activity, and can be viewed as an early and essential biochemical consequence of PNP inhibition culminating in immunosuppression.
authors.affiliation: Immunopathology, Experimental Therapeutics Dept., Parke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48105, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Gilbertsen
authors.forename: M K
authors.initials: MK
authors.lastname: Dong
mesh_terms: D000818:Animals; D003849:Deoxyguanosine / Q000097:blood*; D004492:Edetic Acid; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007288:Inosine / Q000097:blood*; D007700:Kinetics; D008252:Macaca fascicularis; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: C076778:9-deaza-9-(3-thienylmethyl)guanine; D007288:Inosine; D006147:Guanine; D004492:Edetic Acid; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine