Inhibition of ileal bile acid transport by cyclosporin A in rat

Abstract

Abstract. Chronic administration of cyclosporin A may induce cholestasis and this effect has been attributed to impaired hepatic bile salt synthesis, metabolism and transport. We investigated the effect of cyclosporin A on intestinal absorption of bile acids in the ileum of rat. Ileal bile acid absorption was measured by in vivo intestinal perfusion with cyclosporin A and the solvent Cremophor EL. During ileal perfusion with 25 p~ glycocholic acid, the concentration of 2.8 mM cyclosporin A inhibited intestinal bile acid absorption on average by 34%. Additional experiments were performed with everted gut sacs of the distal ileum to evaluate active absorption. A dose and time dependent inhibition of the active intestinal absorption of bile acids was found, with a 50% transport inhibition at an average cyclosporin A concentration of 2.69 mmol L-I . Thus, cyclosporin A inhibits the active intestinal absorption of bile acids which may influence bile acid synthesis, turnover and secretion and may contribute to cyclosporin A induced cholestasis.

Kinetics of primary bile acids in patients after orthotopic liver transplantation

“…Fractional turnover rates of both primary bile acids in patients were not different from control subjects, suggesting that intestinal absorption of bile acids was not influenced by CsA. This is in contrast to rat, in which CsA inhibited the active intestinal absorption of bile acids [19]. Synthesis rates of CA and CDCA were reduced in two of six patients compared with healthy control subjects.…”

“…Possible mechanisms of CsA-induced cholestasis have been attributed to inhibition of bile salt synthesis [9,17], of bile salt uptake at the sinusoidal hepatocyte membrane [14] and of the ATP-dependent export carrier for bile salts at the canalicular membrane of the hepatocyte [18]. In addition, recently, an inhibition of the active intestinal absorption of bile acids by CsA has been demonstrated [19].…”

“…Cyclosporin A (CsA) is used in the immunosuppressive treatment of patients after organ transplantation and may induce cholestasis [7,8]. This effect has been attributed to inhibition of bile salt synthesis [9], impaired uptake of bile salts by the liver [10][11][12][13][14][15], decreased formation of bile acids from cholesterol [16,17], inhibition of the ATP-dependent canalicular export carrier [18] and inhibition of the active intestinal absorption of bile acids [19]. As a consequence, metabolism of bile acids may be impaired.…”

Cystic Fibrosis Related Liver Disease—Another Black Box in Hepatology

“…CSA competitively inhibited sodium dependent uptake and hepatobiliary secretion of radiolabelled taurocholate in animal models [108,109]. In addition, impaired ileal BA absorption was reported after ileal perfusion with CSA in rats [110]. Finally, Hulzebos et al reported effects of chronic CSA treatment on enterohepatic BA circulation.…”

Cyclosporin A and Enterohepatic Circulation of Bile Salts in Rats: Decreased Cholate Synthesis but Increased Intestinal Reabsorption

“…Hepatobiliary secretion of intravenously administered radiolabeled taurocholate was inhibited in bile fistula rats that were acutely or chronically treated with CsA (Kadmon et al, 1993). Finally, CsA may also directly affect bile salt handling by the intestine: ileal perfusion with CsA was shown to impair intestinal bile salt absorption in rats (Sauer et al, 1995).…”