CATABOLISM OF HIRUDIN AND THROMBIN-HIRUDIN COMPLEXES IN THE RAT

The metabolic fate of the anticoagulant protein, hirudin, and its comp lex with thrombin are presently unknown. Therefore we have labelled hi rudin and human thrombin-hirudin complex with the residualizing label dilactitol-I-125-tyramine (I-DLT) in order to identify their tissue s ites of catabolism in the rat. The rapid plasma clearance of hirudin a fter intravenous injection was unaffected by I-DLT labelling, and by 2 h 6 % or less of the injected dose remained in the blood. The majori ty (80.3 +/- 4.0 %, n = 2) of I-DLT-hirudin radioactivity recovered i n tissues was found in kidney, and kidney was also at least 150 times more active in taking up hirudin, on a weight basis, than any other ti ssue examined (liver, spleen, skin, muscle, intestine, fat, lung). I- DLT-hirudin which bound to thrombin was isolated by chromatography on concanavalin A-Sepharose; hirudin itself does not bind to concanavalin A. Radioactivity from thrombin-I-DLT-hirudin was precipitable by ant i-thrombin antibody and I-DLT-thrombin-hirudin was precipitable by an ti-hirudin antibody. By 1 h after injection of labelled thrombin-hirud in complexes, the recoveries of radioactivity from hirudin and thrombi n in liver were comparable (38.6 +/- 3.0 and 36.4 +/- 4.1 % n = 3), wh ereas more radioactivity was recovered in kidney from hirudin than fro m thrombin (27.6 +/- 8.7 compared with 13.6 +/- 4.5 %) and less was re covered in lung (0.4 +/- 0.2 compared with 17.7 +/- 2.9 %). We conclud e that hirudin is catabolized predominantly in kidney, whereas the thr ombin-hirudin complex is catabolized by both liver and kidney.