Human plasma enzymatic degradation

The decapeptide Hoe 140 (6.94), its D- and/or artificial residues being d-Arg, ((4/ )-hydroxy)Pro, (2-thienyl)Ala, D-[(l,2,3,4-tetrahydroisoquinolin-3-yl)carbonyl] and i.-[(3aS, 7aS)-octahydroindol-2-yl carbonyl, is a potent and long-acting antagonist of bradykinin receptors [219][220]. This compound proved highly resistant to enzymatic degradation. It is not a substrate for kini-nase II and carboxypeptidases, and is only slowly degraded in human plasma. 

L. A. Frohman, T. R. Downs, E. P. Heimer, A. M. Febx, Dipeptidylpeptidase IV and Trypsin-Like Enzymatic Degradation of Human Growth Hormone-Releasing Hormone in Plasma , J. Clin. Invest. 1989, 83, 1533-1540. 

Most of the hemiesters 8.136 underwent no or little enzymatic degradation in human plasma, in agreement with the known inertness of hemiesters toward cholinesterase (see Chapt. 7). In contrast, very rapid hydrolysis was usually seen in pig and rat liver preparations, indicating the involvement of carboxylesterases. The only inert compound was the 3,3-dimethylglutarate hemiester of paracetamol (8.136, X = C(CH3)2CH2, Fig. 8.12). Data on the hydrolysis of such prodrugs by human hepatic enzymes will be welcome. 

The acyl derivatives of kallikrein were prepared from porcine pancreatic kallikrein. In our experiments we used benzoyl-kallikrein. By deacylation the enzymatically active kallikrein was generated in plasma from benzoyl-kallikrein demonstrated by means of its amidolytic activity. From the time course of reactivation of benzoyl-kallikrein, a half-time of reactivation of 54 minutes was calculated. Benzoyl- kallikrein was protected from being inactivated by plasma inhibitors. Therefore, the kallikrein activity in plasma was higher after incubation with benzoyl-kallikrein than after incubation with the free enzyme. A comparatively high kinin activity was found in rabbit plasma. In human plasma, this effect was prevented by rapid degradation of kinin [42]. 

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