Beneficial effects of inhibitors of prolyl 4-hydroxylase in CCl4-induced fibrosis of the liver in rats.
S 0885 and HOE 077 inhibit CCl4-induced liver fibrosis in rats, as shown by significantly reduced hydroxyproline content of the liver and improved liver histology. Mortality of drug-treated animals is significantly diminished. Serum collagen parameters correlate well with the hydroxyproline content of the liver and can be used as noninvasive markers for the fibrotic process. HOE 077 is a proinhibitor, which by itself does not inhibit prolyl 4-hydroxylase. HOE 077 is well absorbed from the gastrointestinal tract. It is taken up by rat liver and is converted to the active metabolites. At a concentration of 1 mM, HOE 077 does not affect collagen synthesis in human fibroblasts, bovine chondrocytes and chicken calvaria. At therapeutic doses the compound does not reduce collagen content of kidney, lung, aorta, femur epiphysis, skin and tendon of the rat, validating the high specifity of the liver selective prodrug/inhibitor conversion. From animal experiments, a human daily dose of 0.5-1 g can be extrapolated.
Bickel
M
M
Hoechst, AG, Pharma Research, Frankfurt, Federal Republic of Germany.
Baader
E
E
Brocks
D G
DG
Engelbart
K
K
Günzler
V
V
Schmidts
H L
HL
Vogel
G H
GH
D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000473:pathology; D003094:Collagen / Q000097:blood*; D003238:Connective Tissue / Q000503:physiopathology; D005260:Female; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011347:Procollagen / Q000097:blood; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013718:Tensile Strength; D014945:Wound Healing / Q000187:drug effects
D001647:Bile Acids and Salts; D011347:Procollagen; D011725:Pyridines; C074629:pyridine-2,4-dicarboxylic-diethylamide; C074630:lufironil; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase; D001663:Bilirubin