Effect of bile acids on hepatobiliary transport of cisplatin by perfused rat liver.
The liver and kidney collaborate in the excretion of the cytostatic drug, cis-diamminedichloroplatinum(II) (cisplatin) from the body. Enhancement of this process is envisaged as a way of reducing cisplatin toxicity, thus allowing increases in the doses administered. In this sense, using different compounds, several attempts have been made to enhance cisplatin biliary excretion. In this study, the ability of endogenous compounds belonging to the bile acid family to improve cisplatin excretion by the isolated perfused rat liver was investigated. A highly choleretic bile acid (ursodexoycholic acid) and two others bile acids with marked micelle-forming properties (glycocholic acid and chenodeoxycholic acid) were chosen for study. When these drugs were given at concentrations (1 microM) that did not affect the viability of liver preparations, a correlation between the biliary excretion of platinum and bile acid output was found. This was not due to the incorporation of cisplatin into mixed micelles because no correlation between the biliary output of lecithin or cholesterol and platinum was observed. Moreover, a wash-out effect of bile acids was probably not the cause of bile acid-induced platinum output into bile because no correlation between this and bile flow was found. An enhancement in cisplatin transport processes by the hepatocyte or by direct binding of cisplatin to bile acid monomers or aggregates cannot be ruled out. In spite of the biliary induction of cisplatin output, the net excretion of platinum was reduced under bile acid administration. This was related to lower platinum contents in the liver tissue, probably due to an inhibition of the ability of the hepatocyte to take up and/or retain cisplatin while subject to bile acid infusion. In summary, our results indicate that bile acids reduce the net excretion of cisplatin by the liver even though they induce an enhancement in the transport of this compound from the hepatocyte into bile.
Villanueva
G R
GR
Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, Spain.
Mendoza
M E
ME
el-Mir
M Y
MY
Monte
M J
MJ
Herrera
M C
MC
Marin
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics*; D006000:Glycocholic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010984:Platinum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D002635:Chenodeoxycholic Acid; D010984:Platinum; D014580:Ursodeoxycholic Acid; D006000:Glycocholic Acid; D002945:Cisplatin