Colestimide: the efficacy of a novel anion-exchange resin in cholestatic disorders.

Abstract

See article in J. Gastroenterol. Hepatol. 2002; 17: 697–701 Bile acids are synthesized from cholesterol exclusively in the liver. In normal man, bile acids circulate in the body through a closed circuit called the enterohepatic circulation, that is, from the liver into the intestine and back to the liver. The hepatic cells take up bile acids, and less than 2% of the total bile acid pool spills over into the systemic circulation. Normally, over 90% of the bile acids are reabsorbed from the intestine into the enterohepatic circulation, and only a few percent are excreted in the feces.1 Frequently, patients with cholestasis, such as drug-induced cholestasis, obstructive jaundice and primary biliary cirrhosis (PBC), suffer from severe itching. Ursodeoxycholic acid (UDCA), the 7β-epimer of chenodeoxycholic acid (CDCA), has been shown to be beneficial for the treatment of cholesterol gallstones,2 chronic hepatitis,3,4 and PBC.5–7 Some researchers have previously reported the long-term administration of UDCA to be a safe and effective treatment for the improvement of both biliary enzyme levels and pruritus in PBC.5,6 This was further recognized by many randomized control studies.7,8 More recently, it has been reported in control studies that long-term UDCA therapy delays the development of cirrhosis in PBC.9,10 However, pruritus is said to be recurrent in some studies, as well as in our patients following over 6 years of UDCA administration.9 Under these conditions, the anion-exchange resin cholestyramine is one of the few therapeutic options and is effective in many patients with pruritus associated with cholestatic liver diseases. Recently, colestimide (named as colestilan internationally), a newly developed anion-exchange resin, was used for pruritus associated with cholestatic liver diseases. The absorption of bile acids in the terminal ileum is mediated by an apical sodium-dependent bile acid transporter.11 In contrast, the jejunal bile acid uptake involves mainly passive transport.12 The sodium-independent organic anion transporting polypeptide also transports taurocholic acid in the rat small intestine.13 The bile acid-binding resins were originally designed to control pruritus in patients with cholestasis. The anion-exchange resins exchange chloride ion for negatively charged bile acids. As the anion-exchange resin is not absorbed in the small intestine, the purpose is to decrease intestinal reabsorption, and to consequently increase bile acid excretion in the feces. As a result, the resin depletes the serum of bile acid with a greater affinity for dihydroxy than for trihydroxy bile acids. Furthermore, inhibition of the enterohepatic circulation leads to an increased conversion of cholesterol to bile acid. Cholestyramine has been shown to be clinically beneficial.14 Cholestyramine has been widely used, including renal failure and hematological disorders.15,16 Cholestyramine is effective in many patients with cholestasis-related pruritus. In PBC associated with severe pruritus, cholestyramine is, to date, the sole treatment option. However, the long-term usage of this anion-exchange resin is compromised by poor compliance. Furthermore, because of the resin-bile acid bonding specificity, it is unclear whether UDCA remains equally effective in PBC patients. Indeed, cholestyramine might limit the absorption of UDCA from the small intestine and consequently reduce the efficacy of this bile acid. This matter is clinically relevant and significant. Taha et al. observed that the beneficial effect of UDCA in pruritus could be preserved in PBC patients administered cholestyramine, when the two drugs were taken at least 5 h apart.17 Moreover, Rust et al. examined, in healthy controls, the serum levels of UDCA, the endogenous bile acids and the endogenous bile acid synthesis during simultaneous and separate administration of both UDCA and cholestyramine in vivo.18 These authors also studied the cholestyramine absorption of UDCA both with and without CDCA in vitro.18 The conclusion of these studies was that the administration of cholestyramine and UDCA at an interval of 5 h tended to diminish the effect of cholestyramine on UDCA serum level, and conjugated and unconjugated UDCA were effectively bound by cholestyramine in the presence and absence of hydrophobic bile acids. This led the authors to recommend the administration of UDCA and cholestyramine at different times of day. However, the required daily dose of cholestyramine is so high that it is difficult to administer an effective dose in patients with cholestatic disorders. This consequently leads to poor compliance by the patients. Whereas some other anion-exchange resins are known, they have not been widely used because of their assumed low-binding affinity for bile acids.19,20 Colestimide is a newly developed anion-exchange resin with an imidazolium salt on an epoxide polymer skeleton, which has demonstrated more potent hypolipidemic activity than that of cholestyramine.21 Shimada et al. reported that colestimide presented a higher affinity constant for all bile acids, as well as a greater apparent maximum bile acid binding capacity, except for glycocholic acid, when compared to cholestyramine.22 Colestimide sequesters bile acids and several other lipid components more efficiently than does cholestyramine. Therefore, Shimada et al. speculated that among those clinically relevant resins, colestimide binds bile acids more specifically compared to cholestyramine.22 Moreover, Honda and Nakano reported that colestimide had a greater adsorptive capacity for bile acids than cholestyramine, by a factor of 1.4–2.0-fold when determined in water.21 Suzuki et al. compared the rate of adsorption to colestamine and cholestyramine of 61 drugs whose combination with these anion-exchange resins in a clinical setting was considered probable.23 They demonstrated that the rate of adsorption to colestimide was lower for the majority of the drugs examined than to cholestyramine, suggesting that colestimide affects the absorption of these drugs less than cholestyramine does. It is therefore clear that colestimide has a greater specificity and capacity for bile acids than has cholestyramine. The consequence is that a lesser amount of colestimide than of cholestyramine is required in the treatment of cholestatic patients with pruritus. This should also lead to better compliance by the patients. Colestimide should be proposed as a replacement in the treatment of pruritus in cholestatic patients. Tani et al. reported two cases of drug-induced hepatitis refractory to therapy of UDCA and prednisolone that were immediately relieved of icterus and pruritus following oral administration of colestimide.24 These authors concluded that colestimide would be useful for patients with cholestasis in drug-induced hepatitis, because this agent had few adverse effects and had an easier compliance for the patients. Recently, Yokomori et al. demonstrated the effect of UDCA and colestimide versus UDCA alone on serum bile acids in a randomized open-label study of patients with pruritus.25 A significant improvement in pruritus score was observed after 4 weeks of UDCA and colestimide combination therapy compared with both baseline scores and with scores after 4 weeks of UDCA monotherapy. Although these results are clinically relevant and significant, large-scale trials are needed to elucidate the general efficacy and tolerability of this treatment. Furthermore, Takikawa et al. examined the effect of colestimide in the absorption of UDCA in healthy men.26 They reported that administration of colesti-mide before the meal followed by UDCA administration inhibited the absorption of UDCA to some extent. They indicated that UDCA administration between meals is recommended to maintain the bioavailability of this agent. Although there were some important clinical studies, there are few available basic studies of the relationship between UDCA and colestimide. Moreover, there is little known to clarify the binding affinity of colestimide for various bile acids in particular. In an article presented in a previous issue of the Journal, Onishi et al. determined the bile acid binding property of colestimide.27 The authors demonstrated that the adsorption of bile acids except cholic acid (CA) by colestimide was approximately 60%. In addition, they confirmed the in vivo effect of this resin on bile acid absorption by measuring the excretion of radio-labeled bile acids into bile. Again, the in vivo effect of colestimide on bile acid absorption was obvious, whereas absorption of CA was not inhibited by the presence of colestimide. These authors concluded that the jejunal absorption of UDCA was inhibited by colestimide to a similar extent as that of other dihydroxy bile acids, whereas that of CA remained unchanged. It is important to elucidate the effect of colestimide on the absorption of unconjugated bile acids in the small intestine. The simple and straightforward design of experiments makes this work. However, the authors demonstrated that there is no inhibition of UDCA absorption by 2.5 mg of colestimide in contrast to a marked inhibition of UDCA absorption by 5 mg of colestimide in vivo, but there is the similar extent of adsorption of UDCA with 1 and 5 mg of colestimide. There is a need to clarify the discrepancy in this matter from now on. Further studies are needed regarding the relationship between colestimide and UDCA administration. In summary, the compliance is more satisfactory with colestimide than with cholestyramine. Colestimide is effective for the treatment of jaundice and pruritus. In particular, the combination therapy of colestimide and UDCA could be one of the effective treatments for PBC patients with pruritus. Therefore, colestimide should be considered over cholestyramine as a beneficial therapeutic option in the treatment of cholestatic liver diseases. The author thanks Dr Bernard Bouscarel, Associate Research Professor, Department of Medicine, Division of Gastroenterology and Nutrition, The George Washington University for critically reading the manuscript.