Abstract

Metalloporphyrins, including heme and others that inhibit heme oxygenase, are agents with expanding therapeutic potential. Recent results from our laboratory showed that a combination of heme and zinc-mesoporphyrin was remarkably effective in ameliorating biochemical features of acute porphyria. The aim of this study was to assess plasma clearance, tissue distribution and persistence, stability, toxicology and metabolic effects of zinc-mesoporphyrin, after its i.v. administration to rats. After administration of 15 mumol/kg b.wt. of zinc-mesoporphyrin (bound to serum albumin in a 1:1 molar ratio) the metalloporphyrin was rapidly cleared from plasma (half-life 3.6 h) with uptake primarily into liver and spleen, considerably less into the kidney and none detectable into the heart or brain. Hepatic heme oxygenase activity was undetectable for 4 days and less than 50% of control 1 week later. Inhibition of splenic heme oxygenase activity was also substantial but less marked than in the liver. No mortality was observed in any of the treated animals, and there was no detectable effect on gross or microscopic appearance of the liver, spleen, kidneys, heart, lungs or brain. Blood counts and chemistries remained within normal limits. We conclude that single doses of ZnMP-serum albumin are nontoxic, rapidly cleared from the plasma and persist primarily in the liver and spleen where heme oxygenase is inhibited for prolonged periods.