ABSTRACT
Previously, we found that ONO-2160, an ester-type prodrug of levodopa (3-hydroxy-l-tyrosine), was mainly hydrolyzed in human plasma by α1-acid glycoprotein (AGP) with a partial contribution of albumin. In this study, we investigated whether ONO-2160 was hydrolyzed in the plasma of preclinical species (dog, rabbit, rat, and mouse) and humans and whether AGP and albumin are involved in its hydrolysis. ONO-2160 was hydrolyzed to some extent in the plasma of all tested species with the order of magnitude mouse > human > rabbit > rat > dog. Except for dogs, ONO-2160 was partially hydrolyzed by animal AGP and albumin. This indicated that, similar to albumin, AGP possesses esterase-like activity in mice, rats, and rabbits, as well as humans. A comparison of the values of intrinsic clearance per milliliter of plasma demonstrated that AGP was the major contributor to the hydrolysis of ONO-2160 in rabbit plasma, whereas albumin was primarily responsible for the hydrolysis of ONO-2160 in mouse plasma. This was confirmed by experiments using AGP-knockout mouse plasma. This study reports the first evidence for the existence of species differences in the hydrolysis of ONO-2160 in plasma related to the different contributions of AGP and albumin.
Subject(s)
Levodopa/pharmacokinetics , Orosomucoid/metabolism , Animals , Dogs , Esters/chemistry , Esters/pharmacokinetics , Healthy Volunteers , Humans , Hydrolysis , Levodopa/chemistry , Male , Mice , Mice, Knockout , Orosomucoid/genetics , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Rabbits , Rats , Species SpecificityABSTRACT
OBJECTIVE@#To investigate the expression of brain natriuretic peptide (BNP) in rat myocardial tissue after acute cardiac dysfunction and to explore the role of BNP in diagnosis of cardiac dysfunction in forensic practice.@*METHODS@#Rat models of acute cardiac dysfunction were established. The expression of BNP protein and BNP mRNA in myocardial tissue after cardiac dysfunction were detected by immunohistochemistry, Western blotting and real-time RT-PCR.@*RESULTS@#The extent of positive staining of BNP increased over the time course during cardiac dysfunction. The expression of BNP showed mild positive in cardiomyocytes from 1 h to 2 h. From 4 h to 6 h, the expression was moderate positive. From 10 h to 12 h, the BNP showed a strongest positive expression. The expression of BNP presented a significant raise with the increasing time of cardiac dysfunction by Western blotting and real-time RT-PCR. The expression of BNP mRNA increased significantly 1 h after cardiac dysfunction.@*CONCLUSION@#Investigating the expression of BNP protein and BNP mRNA in myocardial tissue may provide a new approach to evaluate the cardiac function for forensic pathologists.
