Evidence of drug interaction between cyclosporin A and H2-receptor antagonists (cimetidine, ranitidine and famotidine) in Sprague-Dawley rats.
H2-receptor antagonists, such as cimetidine (C), ranitidine (R) and famotidine (F) seem to be effective in the prevention and treatment of stress ulcer in transplant recipients receiving cyclosporin A (CyA). The aim of this study was to detect the possible synergistic nephro- and hepato-toxicity of these drugs, assaying the serum creatinine (SC), ALT, AST levels, and the histological features of 45 young male Sprague-Dawley rats, divided into nine groups of five rats each. After 10 days of treatment the results showed: (i) serum CyA levels were increased in the group receiving daily CyA (5 mg/kg) + R(5 mg/kg) (2430 +/- 403 ng/ml; p less than 0.05 vs. controls) and in the group receiving daily CyA (5 mg/kg) +/- C (10 mg/kg) (2440 +/- 265 ng/ml; p less than 0.01 vs. controls); (ii) ALT and AST levels were increased in this latter group (ALT 223 +/- 133 UL, AST 114.67 +/- 39 UL; p less than 0.01 vs. controls); (iii) SC levels were normal; and (iv) steatosis of the liver was observed in these two groups. These findings suggest that C and R, but not F, may inhibit the hepatic cytochromes P-450 which are involved in the oxidative metabolism of the drugs. Furthermore, the high serum CyA levels seem to play a major role in the appearance of biochemical and histological damage to the liver.
Filingeri
V
V
Surgical Clinic, University of Rome Tor Vergata, Italy.
Giacomelli
R
R
Famularo
G
G
Rosati
R
R
Nardi
S
S
Calogero
A
A
Iacona
A
A
Stortoni
F
F
Cramarossa
L
L
Sacchetti
S
S
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002927:Cimetidine / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D003524:Cyclosporins / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D015738:Famotidine; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology
D003524:Cyclosporins; D006635:Histamine H2 Antagonists; D013844:Thiazoles; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase