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Models to explain the pathophysiology of protoporphyria have been based on fluxes of protoporphyrin between plasma and liver for which no quantitative data exist. The present studies employed isolated, in situ, recirculating and nonrecirculating rat liver perfusions to define the kinetics of hepatic uptake and biliary secretion of protoporphyrin. Livers from Sprague-Dawley rats were perfused with Krebs-Henseleit-3% albumin solution (bile acid-free) to which protoporphyrin was added. In nonrecirculation studies, hepatic protoporphyrin extraction was determined from 5 sec to 3 min. In recirculation studies, protoporphyrin perfusate disappearance and biliary secretion were determined at 5 and 10 min intervals, respectively. Rate constants derived from compartmental analysis of recirculation studies correlated with early measured values obtained during nonrecirculation; however, a dose-related decrease in the influx rate constant was evident. The overall disappearance of protoporphyrin from perfusate followed first-order kinetics but was neither monoexponential nor saturable. Sinusoidal cells contained less than 8% of the protoporphyrin extracted by the liver. Only 0.1% to 4% of the extracted protoporphyrin was secreted into bile. Therefore, canalicular secretion appeared to be the rate-limiting step in hepatic protoporphyrin disposal. Extrapolations based on these data provide a theoretical framework to appreciate the generation of plasma protoporphyrin concentrations. Within this framework, it may be inferred that if plasma protoporphyrin concentration is in excess of that predicted from total protoporphyrin excretion, a defect in hepatic protoporphyrin clearance exits.