Pharmacokinetics of aminoguanidine administration and effects on the diabetes frequency in nonobese diabetic mice.

Abstract

In vitro studies suggest that intra-islet nitric oxide production may contribute to the pathogenesis of autoimmune insulin-dependent diabetes mellitus. We tested whether aminoguanidine (AG), a competitive inhibitor of inducible nitric oxide synthase, might block beta cell destruction and prevent insulin-dependent diabetes mellitus in vivo. A total of 50 female nonobese diabetic mice, from the time of weaning until 32 wk of age, received injections (i.p.) twice daily with 50 mg AG/kg body weight and received AG in drinking water (350 mg/liter). A total of 50 littermates treated with vehicle alone served as controls. A 24-hr pharmacokinetic analysis showed that AG was readily absorbed after i.p. administration, peaked in plasma (9.0 micrograms/ml) at 0.5 hr and had a half-life of 1.88 hr. Steady-state values for the area under the curve for the therapeutic regimen were 20.51 and 16.35 (micrograms)(hr)/ml for the 0000 to 1600 and 1600 to 2400 hr, respectively. In terms of therapy, life-table analysis indicated the frequency of insulin-dependent diabetes mellitus (6/30 AG-treated vs. 11/31 vehicle-treated, P = .25) and insulitis scores (2.0 +/- 1.1 vs. 2.4 +/- 1.2 in nondiabetic AG- and vehicle-treated mice at 32 wk, respectively, P = .20) were similar in both groups. Flow cytometric analysis revealed no quantitative differences in islet infiltrating macrophages, CD4+ or CD8+ T lymphocytes between groups of animals randomly killed at 8, 16 and 32 wk. Although not eliminating a role for nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus, prophylactic treatment with AG did not significantly impact the onset of insulitis or diabetes in nonobese diabetic mice.

• Authors: M A Bowman, O G Simell, A B Peck, J Cornelius, R Luchetta, Z Look, N K Maclaren, M A Atkinson
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 279 Issue 2 Pg. 790-4 (Nov 1996) ISSN: 0022-3565 [Print] United States
• PMID: 8930185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Guanidines
• Nitric Oxide
• Nitric Oxide Synthase
• pimagedine

Topics

• Animals
• Diabetes Mellitus, Type 1 (drug therapy)
• Enzyme Inhibitors (pharmacokinetics)
• Female
• Guanidines (pharmacokinetics, therapeutic use)
• Islets of Langerhans (pathology)
• Mice
• Mice, Inbred NOD
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase (antagonists & inhibitors)