Improvement of cyclosporin A-induced cholestasis by tauroursodeoxycholate in a long-term study in the rat.
Cyclosporin A is an essential immunosuppressive drug, but it is potentially toxic to the kidney and liver. Ursodeoxycholic acid, a hydrophilic bile acid, has been reported to improve cholestasis in liver disease in man. The purpose of this work was to examine whether tauroursodeoxycholate could reduce cyclosporin A-induced hepatic or renal injuries in the rat. After randomization into three groups (N = 8), rats received daily for 17 days: cyclosporin A intraperitoneally alone (30 mg/kg) or cyclosporin A intraperitoneally and tauroursodeoxycholate (60 mg/kg) by gavage; control received the cyclosporin A excipient. Under tauroursodeoxycholate, cholestatic parameters (bile flow, bile salt secretion, serum bile salts, serum bilirubin) improved significantly without affecting cyclosporin A blood levels, and excretion of the drug and its metabolites in bile increased by 47%. Serum creatinine levels were better preserved, although not significantly. These results show that tauroursodeoxycholate prevents cyclosporin A-induced cholestasis in long-term treatment in rats, possibly by facilitating the drug elimination in bile.
INSERM, Marseille, France.
P E
PE
Queneau
P
P
Bertault-Peres
M
M
Guitaoui
E
E
Mesdjian
A
A
Durand
J C
JC
Montet
D000818:Animals; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000633:toxicity*; D007536:Isomerism; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000627:therapeutic use*
D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D016572:Cyclosporine