Pharmacokinetics of aprotinin in preoperative cardiac surgical patients

Aprotinin, a polypeptide protease inhibitor, reduces bleeding and transfusion requirements during cardiac surgery. To investigate aprotinin's pharmacokinetics, we administered therapeutic doses to patients scheduled to undergo cardiac surgery.

Preoperative doses of 500,000 and 1,000,000 kallikrein inhibitor units (KIU) were administered as an infusion over 30 min to 28 patients, and plasma concentrations were measured for 48 h. Aprotinin concentrations were determined using a sandwich-enzyme-linked immunosorbent assay. A three-compartment model was fit to the measured aprotinin concentrations using extended nonlinear least-squares regression.

Plasma aprotinin concentrations at the end of the 30-min infusion were 147 +/- 61 KIU/ml for the 1,000,000-KIU dose and 60 +/- 19 KIU/ml for the 500,000-KIU dose. Elimination clearance was 35.5 ml/min, and volume of distribution at steady state was 26.5 l.

A 2,000,000-KIU dose is needed to produce the plasma concentration of 200 KIU/ml associated with kallikrein inhibition. Plasma concentrations in excess of 50 KIU/ml, the concentration required to inhibit plasmin, can be achieved by a significantly smaller dose. Based on the derived pharmacokinetic parameters, an infusion model was developed to appropriately administer and maintain effective plasma concentrations of aprotinin, depending on the plasma concentration desired and the target proteases to be inhibited.