SYNTHESIS AND BIODISTRIBUTION OF BOWMAN-BIRK SOYBEAN PROTEASE INHIBITOR CONJUGATE WITH AMPHIPHILIC POLYESTER

The modification of Bowman-Birk soybean protease inhibitor (BBI) with the monoaldehyde derivative of block copolymer of ethylene oxide and p ropylene oxide (PE), M(r) 2000 is described. The conjugate contains fi ve covalently bound polymer chains per protein molecule, and retains t he ability to inhibit trypsin and chymotrypsinlike proteinases. The di stribution of native BBI and the BBI-PE conjugate was examined in mice . After iv injection of [I-125]BBI and [I-125]BBI-PE, both inhibitors distributed very rapidly to the liver, kidney, and lungs, and more slo wly to the brain. At the same time-points (up to 24 h), radioactivity in the blood and organs of mice injected with modified inhibitor was h igher than that of the native inhibitor. The blood concentration time profile following iv administration of two BBI preparations at a dose 3 mg/kg was reasonable well described by a two-compartment open model with first-order elimination kinetics. The total clearance of BBI-PE d ecreased by a factor of 8, body mean residence time increased by a fac tor of 5 in comparison with BBI. A physiological pharmacokinetic model was developed to describe the tissue-to-blood distribution of two inh ibitors. One-compartment physiological organ model (flow limited) was used to describe of timecourse profiles of BBI concentration in organs . A two-compartment physiological organ model (membrane limited) was u sed to predict tissue-to-blood distribution of conjugated BBI in some organs of mice (liver, lungs). The predicted concentration curves of B BI and BBI-PE in blood and organs in mice (with the exception of kidne y) showed good agreement with the observed values.