IN-VIVO I-125 ERYTHROPOIETIN PHARMACOKINETICS ARE UNCHANGED AFTER ANESTHESIA, NEPHRECTOMY AND HEPATECTOMY IN SHEEP

Knowledge regarding the in vivo metabolic fate of the glycoprotein ery thropoietin (EPO) is incomplete. To determine whether EPO pharmacokine tics are perturbed by ablation of the kidneys or liver or by anesthesi a, EPO pharmacokinetic parameters were determined in adult sheep. Anim als were studied in a paired manner, with and without deep barbiturate anesthesia and before and immediately after nephrectomy or hepatectom y accompanied by deep barbiturate anesthesia. Hepatectomy was accompli shed with the liver left in situ, by occlusion of the arterial hepatic blood supply and diversion of portal venous flow to the jugular vein. After i.v. administration of tracer amounts of I-125-labeled recombin ant human EPO, multiple blood samples were taken over 6 to 7 hr and an alyzed for EPO immunoprecipitable radioactivity. EPO pharmacokinetic p arameters were derived using a noncompartmental system analysis applie d to the data on EPO immunoprecipitable radioactivity. No significant differences were detected for plasma clearance, distribution volume, m ean residence time and a! and beta half-lives examined under each of t he three paired study conditions. Contrary to speculation by others, r esults of the present study make it highly unlikely that removal of th e terminal sialic acid moieties of EPO contributes significantly to th e metabolism of EPO. Because removal of the liver and kidney had no ef fect on EPO elimination, the metabolic degradation of EPO occurs in a tissue compartment that is yet to be defined. We speculate that the bo ne marrow is the most likely tissue with primary responsibility for th e metabolism of EPO.