DISPOSITION OF TIN-PROTOPORPHYRIN AND SUPPRESSION OF HYPERBILIRUBINEMIA IN HUMANS

Tin (Sn4+)-protoporphyrin, a potent competitive inhibitor of heme degradation to bile pigment, was cleared rapidly from plasma in normal subjects (t1/2 .apprx. 4 hours for plasma levels > 5 nmol/ml, with evidence of dose-dependent pharmacokinetics at lower plasma concentrations). Small amounts were excreted promptly in urine (0.1% to 5.6%) and more gradually in feces (3.7% to 11.3%). The only dose-limiting (> 1.0 .mu.mol/kg, single dose) side effect was mild sensitivity to sunlight and long-wave ultraviolet light. Absorption after intramuscular administration was rapid, but there was no absorption after oral dosing. In bile duct-ligated rats treated with Sn-protoporphyrin, there was a substantial (approximately 50%) reduction in plasma bilirubin levels compared with levels in ligated control animals. Seven studies were carried out in four women with moderate to severe cholestasis secondary to primary biliary cirrhosis and in two men with Gilbert''s syndrome. In these studies Sn-protoporphyrin (total doses of 0.25 to 2.0 .mu.mol/kg body weight) reduced plasma bilirubin levels to a varying degree (7% to 43%) promptly after its intravenous administration.