Influence Of Cholestyramine Research Articles

Influence of cholestyramine on the pharmacokinetics of rosiglitazone and its metabolite, desmethylrosiglitazone, after oral and intravenous dosing of rosiglitazone: Impact on oral bioavailability, absorption, and metabolic disposition in rats

The possible influence of the bile acid-sequestering agent cholestyramine (CSA), which is a basic co-medication in hypercholesterolemic patients, on the pharmacokinetics of rosiglitazone (RGL) and its circulating metabolite desmethylrosiglitazone (DMRGL) was investigated following a single oral and intravenous dose of RGL to Wistar rats. The pharmacokinetic parameters of RGL and DMRGL were evaluated following oral or intravenous administration of RGL to rats at 10 mg kg−1 with and without pre-treatment (0.5 h before RGL administration) of CSA at 0.057, 0.115, 0.23 and 0.34 g kg−1 doses. With an increase in CSA dose there was dose-dependent decrease in area under the curve (AUC)(0−∞) and Cmax with no change in Tmax, Kel and t1/2 values for both RGL and DMRGL following oral administration of RGL. The oral bioavailability of RGL was reduced by 19.9, 35.6, 53.8 and 72.0% in rats following pre-treatment with CSA at 0.057, 0.115, 0.230 and 0.340 g kg−1, respectively. There was no change in the above-mentioned pharmacokinetic parameters for RGL and DMRGL in rats when RGL was given intravenously following pre-treatment with the above-mentioned oral doses of CSA. Another objective of the study was to determine the effect of staggered oral CSA dosing at 1, 2 and 4 h after oral RGL administration at 10 mg kg−1. AUC(0−∞) of RGL and DMRGL was reduced following CSA staggered administration at 1 h, whereas 2- and 4-h staggered dose administration of CSA had no effect on the AUC(0−∞) of RGL and DMRGL. Irrespective of CSA staggered dose administration there was no change in other pharmacokinetic parameters, namely Cmax, Tmax, Kel and t1/2. The apparent formation rate constant (Kf) of DMRGL was also calculated to show that only the absorption of RGL was affected, not the apparent formation rate of DMRGL. The authors also studied the in vitro adsorption of RGL (100, 250, 500 µg ml−1) at various pH conditions (pH 2, 4 and 7) and different concentrations of CSA (15, 30, 60 and 120 mg ml−1). The percentage binding of CSA was in the range 50–72% (at pH 2), 74–89% (at pH 4) and 97–100% (at pH 7). In conclusion, we carried out a systematic investigation demonstrating mechanistically the interaction potential of RGL when co-administered with CSA. The applicability of the metabolite data after intravenous and oral dosing and pH-based binding experiments further adds credence to the key findings.

Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine.

Cholestyramine is an effective drug for the reduction of plasma cholesterol because of its ability to sequester intestinal bile acids. Since metabolic alterations, including diminished intestinal absorption of vitamin D and osteomalacia have been reported with long-term use of this resin, the influence of cholestyramine on dietary balance of four mineral elements has been investigated. Wistar-strain rats were fed either a 2% cholestyramine or control diet for one month. Dietary intakes and fecal and urinary excretions of calcium, magnesium, iron, and zinc were determined using atomic absorption spectrophotometry during three, 3-day balance periods. Cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for magnesium, iron, and zinc than the controls. Other effects of cholestyramine were an increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine. Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone. A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.

Protective effects of cholestyramine on liver cirrhosis induced by carbon tetrachloride in the rat.

The influence of cholestyramine and chenodeoxycholic acid on the induction of liver cirrhosis by carbon tetrachloride was investigated in the Wistar rat. The addition of 1.3% cholestyramine to the diet of the experimental animals inhibited to a large extent the induction of cirrhosis. While all the animals subjected to carbon tetrachloride exposure plus basal diet and those to carbon tetrachloride intoxication plus chenodeoxycholic acid diet developed cirrhosis, the morphological manifestation of cirrhosis occurred in the livers of only two out of 18 rats under carbon tetrachloride treatment plus cholestyramine diet. The administration of cholestryamine induces reactions which correspond to the physiological protective mechanisms of the liver. These are the bile acid binding, bacteriostatic, and microsomal enzymatic stimulating properties of cholestyramine.

Influence of cholestyramine on synthesis of cholesterol and bile acids in germfree rats.

The present investigation describes the influence of partial, pharmacologic interruption of bile acid enterohepatic circulation on cholesterol and bile acid synthesis in germfree rats. Seven rats received a basal, semisynthetic diet and five rats received the basal diet supplemented with 5% cholestyramine. After 6 weeks, feces were collected in one 3- and one 4-day pool for analysis of bile acids and cholesterol. When the sampling period was concluded, the rats were killed and the liver microsomal fractions were isolated. The activities of HMG CoA reductase and 7alpha-hydroxylase were determined. The main fecal bile acids in the untreated rats were cholic acid and beta-muricholic acid. During cholestyramine treatment cholic acid increased from 4.4 +/- 0.7 to 39.5 +/- 5.6 mg/kg body weight/day and beta-muricholic acid from 4.5 +/- 0.6 to 7.7 +/- 0.9 mg/kg body weight/day. Chenodeoxycholic acid became a major bile acid averaging 10.4 +/- 1.6 mg/kg body weight/day. The total amount of bile acids increased about 6-7 times and the percentage of cholic acid increased from 49.4 +/- 2.0 to 68.6 +/- 1.1%. The 7alpha-hydroxylase activity increased 4-5 times. During cholestyramine treatment the fecal excretion of cholesterol was increased from 12.0 +/- 1.4 to 68.0 +/- 5.0 mg/kg body weight/day. The endogenous formation of cholesterol was increased 6 times and the HMG CoA reductase activity was increased about 20 times. In conclusion, germfree rats, like conventional rats, have the ability to increase the endogenous formation of bile acids and cholesterol during interruption of the enterohepatic circulation of bile acids, which is also reflected in a stimulation of the activities of the rate-determining enzymes.

Role of Bile Acid Malabsorption in Pathogenesis of Diarrhea and Steatorrhea in Patients with Ileal Resection

Balance studies, which focused on bile acid metabolism, were carried out on 9 patients with ileal resection in order to define the importance of bile acid malabsorption in the pathogenesis of the diarrhea and steatorrhea. The influence of cholestyramine (Q) or type of dietary fat—long chain triglyceride (LCT) or equicalorically substituted medium chain triglyceride (MCT)—on bile acid synthesis, diarrhea, steatorrhea, and fecal electrolyte excretion was measured during steady state intervals of four randomized periods (LCT, LCT + Q, MCT, and MCT + Q). During control (LCT) periods, all patients had bile acid malabsorption, excreting >75% of administered taurocholate-14C within 24 hr, and this malabsorption was accompanied by a 10- to 20-fold increase in bile acid synthesis. Patients with ileal resection of less than 100 cm had greatly increased concentrations of bile acids in fecal water compared with normal control subjects. Administration of cholestyramine significantly decreased fecal weight, frequency, and sodium ion excretion as well as the concentration of bile acid in fecal water. These observations, together with our previous demonstration that bile acids induce water and electrolyte secretion by the human colon, provide evidence that a major cause of diarrhea in these patients was the increased passage of bile acids into the colon. Cholestyramine caused the already increased bile acid synthesis to increase still more in some of these patients; maximal synthesis was 0.1 to 0.3 mmole per kg of body weight per day, based on gas chromatographic measurements of fecal bile acids. All patients had mild steatorrhea ( 20 g per day); fat malabsorption appeared to be a major cause of diarrhea, since replacement of LCT by MCT caused a decrease in fecal weight, sodium, and potassium as well as a striking decrease in steatorrhea. Unabsorbed fatty acids were converted in part to hydroxy fatty acids by intestinal bacteria and it is proposed that unabsorbed fatty acid or its bacterial product, hydroxy fatty acid, or both, contributed to diarrhea. Bile acid malabsorption appeared to play no direct role in the diarrhea in 2 of 3 patients, since there ~ was no response to cholestyramine and the concentration of bile acids in fecal water was low. Malabsorption of bile acids was nonetheless important in the syndrome, since jejunal bile acid concentrations were decreased (causing fat maldigestion) in 2 of 3 patients, and fat maldigestion, together with decreased mucosal surface, was the probable explanation for the severe steatorrhea. These studies define two syndromes of bile acid malabsorption, present evidence for different mechanisms of diarrhea in each, and describe a therapeutic program.

Effect of cholestyramine on composition of duodenal bile in obese human subjects

The effects of the oral hypocholesterolemic drug, cholestyramine (16 g/day), upon the composition of duodenal bile were studied in four obese, normolipidemic subjects (three female, one male) while they slowly lost weight during prolonged periods of constant liquid formula feeding on the metabolic ward. Four-week periods of drug treatment (during which the anticipated lowering of plasma total cholesterol level occurred) were alternated with similar periods without treatment or with administration of placebo. Fasting duodenal bile samples were obtained at intervals by intubation followed by intravenous cholecystokinin and were analyzed for cholesterol, total phospholipid, and both total and individual bile acids. Cholestyramine treatment resulted in large and significant changes in the relative proportions of the major individual bile acids, which were reversible when the drug was withdrawn. The primary (hepatic-synthesized) cholic acid was increased from 38.0 ± 1.6% (mean ± SE) to 67.3 ± 1.4%; primary chenodeoxycholic acid was decreased from 37.4 ± 1.4% to 26.1 ± 1.1%; and secondary (bacterially modified) deoxycholic acid was decreased from 25.0 ± 2.0% to 6.6 ± 0.8%. The greatly increased rate of hepatic bile acid synthesis under the influence of cholestyramine was probably partly responsible for these changes. In addition, the ratio of glycine-conjugated to taurine-conjugated bile acids in duodenal bile was greatly increased during cholestyramine treatment (from 2.7 ± 0.2% to 7.3 ± 0.6%), so that glycocholic acid became the predominant conjugated bile acid. Evidence that these marked bile composition changes are either beneficial or otherwise in relation to cholelithiasis is not available, but their occurrence should be borne in mind in considering long-term use of cholestyramine or similar bile acid sequestering substances as hypocholesterolemic agents.

Influence of Cholestyramine, Bile Salt, and Cholesterol Feeding on the Lipid Composition of Hepatic Bile in Man

Influence of Cholestyramine, Bile Salt, and Cholesterol Feeding on the Lipid Composition of Hepatic Bile in Man

The influence of cholestyramine on thyroxine absorption

Cholestyramine resin, an anionic exchange resin, currently being investigated as an agent for lowering serum cholesterol levels, has been shown to interfere with the absorption of ingested thyroid hormone. A small quantity of the resin is capable of binding thyroxine under the conditions encountered in the gastrointestinal tract. Interference with thyroid hormone absorption by cholestyramine can be minimized by allowing a time interval of at least four hours between the ingestion of the two agents. Hypothyroid patients receiving cholestyramine should be examined periodically for evidence of hypothyroidism, and adjustments in dose and time interval between the two agents should be made if malabsorption of thyroid hormone is significant.