TISSUE DISTRIBUTION OF ZINC-MESOPORPHYRIN IN RATS - RELATIONSHIP TO INHIBITION OF HEME OXYGENASE

Metalloporphyrins, including heme and others that inhibit heme oxygena se, are agents with expanding therapeutic potential. Recent results fr om our laboratory showed that a combination of heme and zinc-mesoporph yrin 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 metabo lic effects of zinc-mesoporphyrin, after its i.v. administration to ra ts. After administration of 15 mu mol/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 in to liver and spleen, considerably less into the kidney and none detect able into the heart or brain. Hepatic heme oxygenase activity was unde tectable for 4 days and less than 50% of control 1 week later. Inhibit ion of splenic heme oxygenase activity was also substantial but less m arked than in the liver. No mortality was observed in any of the treat ed animals, and there was no detectable effect on gross or microscopic appearance of the liver, spleen, kidneys, heart, lungs or brain. Bloo d counts and chemistries remained within normal limits. We conclude th at single doses of ZnMP-serum albumin are nontoxic, rapidly cleared fr om the plasma and persist primarily in the liver and spleen where heme oxygenase is inhibited for prolonged periods.