TISSUE DISTRIBUTION AND DISPOSITION OF TIN-PROTOPORPHYRIN, A POTENT COMPETITIVE INHIBITOR OF HEME OXYGENASE

Abstract

Tin(Sn)-protoporphyrin is a potent competitive inhibitor of heme oxygenase and can suppress naturally occurring or experimentally induced hyperbilirubinemia in animals. The plasma clearance of Sn-protoporphyrin, its persistence in tissues and the time course of heme oxygenase inhibition up to 7 days after administration of doses up to 50 .mu.mol/kg b.w. [body wt] to adult male rats were studied. After s.c. doses the metalloporphyrin was rapidly and almost completely absorbed. Initial plasma clearance was log-linear with a T1/2 [half-life] of approximately 3 h after either i.v. or s.c. administration. Levels of Sn-protoporphyrin in most tissues rose during the first 2 h and persisted for up to 7 days. Concentrations were highest in kidney and liver, were considerably lower in spleen, lung, intestine, adrenal and testes, and as Sn-protoporphyrin concentrations in plasma declined, concentrations in these tissues eventually exceeded simultaneous plasma concentrations. This suggests a varying degree of uptake and binding of the metalloporphyrin in these tissues. There was little or no uptake of Sn-protoporphyrin in heart, brain and red cells. Markedly decreased heme oxygenase activity in liver, kidney and spleen persisted as did Sn-protoporphyrin up to 7 days. The total amount of Sn-protoporphyrin present in tissues and excreta was a fairly constant fraction of the dose (.apprx. 50%) at time intervals up to 7 days after injection. Single doses of Sn-protoporphyrin are evidently rapidly cleared from plasma and persist in tissues and potently inhibit heme oxygenase activity for prolonged periods. [Sn-protoporphyrin may be potentially applicable to the treatment of jaundice in humans when excess bilirubin accumulation is considered to be harmful, as in the severe hyperbilirubinemia which is common in premature or underweight infants.].