The effect of the apolipoprotein E phenotype on cholesteryl ester transfer protein activity, plasma lipids and apolipoprotein A I levels in hypercholesterolaemic patients on colestipol and lovastatin treatment.

BACKGROUND: Apolipoprotein E (apo E) allele E 4 is associated with high atherogenic lipid levels and coronary heart disease. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from (high density lipoprotein) HDL to other lipoproteins. CETP gene expression is enhanced in hypercholesterolaemia and correlates with plasma apo E concentration. OBJECTIVE: The effect of the apo E phenotype on plasma CETP activity and the hypolipidaemic efficacy of colestipol and lovastatin was studied in patients with type II a or II b hypercholesterolaemia. RESULTS: The baseline mean plasma total, low density lipoprotein (LDL) and HDL cholesterol, triglyceride, apolipoprotein A I (apo A I) concentrations and CETP activity were 8.89 mmol x l(-1), 6.78 mmol x l(-1), 1.39 mmol x l(-1), 1.59 mmol x l(-1), 1.49 g x l(-1) and 114 nmol x h(-1) x ml(-1), respectively. The colestipol-induced changes were -26%, -36%, +5%, + 12%, -1% and -17%, and the lovastatin-induced changes -34%, -44%, +6%, -18%, +1% and -19%. The lipid and apo A I concentrations or the CETP activity did not differ statistically significantly according to the apo E phenotype, although the HDL cholesterol and apo A I levels were lowered in patients with apo E 4/4 but elevated in patients with the other phenotypes. The CETP activity correlated with the LDL cholesterol concentration (r = 0.52, P = 0.01) and the change in the LDL cholesterol during colestipol (r = 0.51, P = 0.02) and lovastatin (r = 0.65, P = 0.001) treatment, but only in patients without the apo E 4 allele. CONCLUSION: Colestipol and lovastatin reduced CETP activity to the same amount, regardless of the apo E phenotype. The apo E phenotype seems to modify the interaction between CETP activity and LDL cholesterol in hypercholesterolaemia and during pharmacological lowering of cholesterol.

Acción hipocolesterolemica de la colestina en conejos normocolesterolémicos / Hypocholesterolemic action of cholestine in normal cholesterolemic rabbits

Se valora el efecto de la colestina sobre algunos parámetros lipídicos, así como de la coagulación en conejos Nueva Zelandia machos durante 45 días. El grupo de animales que recibió colestina muestra una disminución significativa de los niveles de colesterol total al finalizar el estudio (p<0,05)no así el grupo control; el resto de los parámetros lipídicos y de la coagulación evaluados no muestran cambios significativos. Los resultados obtenidos en esta investigación muestran que la colestina en la dosis utilizada es capaz de disminuir el colesterol sérico sin afectar los otros parámetros lipídicos y de la coagulación estudiados (AU)

Quaternized colestipol, an improved bile salt adsorbent: in vitro studies.

Colestipol.HCl (col-HCl) was quaternized with methyl iodide to form col-CH3l. The in vitro binding capacities of the quaternized and protonated resins in water and in Tris-HCl buffer (0.0015 and 0.0025 M, pH 7.0) at approximately 22 degrees C for sodium glycocholate (NaGC) was determined by reversed-phase HPLC. The binding capacities were found to depend on the adsorption medium. In water, the binding capacity of col-CH3l was 30% greater than that of its protonated form. In Tris-HCl buffer at pH 7.0, the binding capacities of the resins were similar. When the quaternized colestipol was converted to its chloride form, the binding capacity for NaGC in Tris-HCl increased significantly and was 30% greater than that for its protonated analogue. In Cotazym 65B-water, a medium used to test the binding capacity of the resins in the presence of various agents (to try to simulate intestinal conditions), the binding capacity of the quaternized resin was again greater than that of its protonated form. Quaternization thus increases the in vitro binding capacity of colestipol for the glycocholate anion.

The effects of charcoal and sorbitol (alone and in combination) on plasma theophylline concentrations after a sustained-release formulation.

1. The effects of charcoal and sorbitol, alone and in combination, were investigated in eight healthy female volunteers who received 600 mg slow-release theophylline (two 300 mg capsules). 2. The area under the plasma concentration time curve to 24 h (AUC0-24) after theophylline alone was significantly greater than after both the charcoal and charcoal plus sorbitol phase. 3. Charcoal and charcoal with sorbitol also significantly reduced the maximum plasma theophylline concentration (Tmax) and time to maximum concentration (Cmax). 4. Sorbitol significantly increased Cmax and shortened Tmax. 5. Although sorbitol did not reduce the adsorptive efficacy of charcoal, its use alone may be deleterious in poisoning with sustained-release theophylline products.

[Pharmacokinetics of fenofibrate in man (author's transl)]. / Pharmacocinétique du fénofibrate chez l'homme.

The active metabolite of fenofibrate is fenofibric acid, which is strongly bound to serum proteins. Following a single oral dose of 300 mg fenofibrate there is a diphasic decrease in plasma levels of fenofibric acid, and most of the drug is excreted as conjugate in the urine. Following daily oral administration of 300 mg during 10 days, a state of equilibrium is obtained within 2 to 3 days and persists throughout the observation period; the mean elimination half-life and urinary excretion rate are very similar to those measured after a single dose, and the drug does not accumulate. In patients with renal insufficiency, the plasma half-life of fenofibric acid is very substantially prolonged and considerable accumulation takes place, as the compound is virtually not dialyzable. Doses of 100 mg/day produce plasma levels similar to those obtained with 300 mg/day. The lipid-lowering activity mostly affects triglycerides. Concomitant administration of colestipol has no effect on blood kinetics and urinary excretion of fenofibrate but results in very important reduction of all lipoprotein fractions.

Lack of pharmacokinetic interaction of colestipol and fenofibrate in volunteers.

The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 microgram/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs.

Colestipol: a review of its pharmacological properties and therapeutic efficacy in patients with hypercholesterolaemia.

Colestipol is an anion exchange resin with bile acid sequestering properties resembling those of cholestyramine, another lipid-lowering binding resin. In daily doses of 15 to 30g colestipol reduces total plasma cholesterol concentrations (primarily low density lipoprotein cholesterol) by about 15 to 30%, but plasma triglyceride concentrations may be unchanged or in some patients increased. Thus, like cholestyramine, colestipol is of benefit in patients with primary hypercholesterolaemia without associated hypertriglyceridaemia (type IIa hyperlipoproteinaemia). Colestipol is odourless and tasteless, and is said by some to be more readily tolerated by patients than cholestyramine, leading to improved compliance, but such data has not been documented in most studies. Side effects of colestipol treatment are primarily gastrointestinal in nature since the drug is essentially unabsorbed. As with cholestyramine, colestipol may bind with other concomitantly administered drugs reducing their absorption or enterohepatic recirculation; dosage intervals of other concurrent medications should be adjusted to minimise the potential for such an interaction.

In vitro binding of various biological substances by two hypocholesterolaemic resins. Cholestyramine and colestipol.

The ability of cholestyramine and colestipol, two hypocholesterolaemic resins, to bind in vitro several compounds such as vitamin B12, vitamin B12-intrinsic factor complex, folic acid, iron citrate and calcium chloride was investigated. Both resins bound to a high extent vitamin B12-intrinsic factor complex, folic acid and iron citrate; in addition, cholestyramine also caused appreciable binding of calcium. Throughout a large range of pH, there was no change in the binding capacity; however, at pH 2, cholestyramine exhibited a marked drop in the binding of tested substances (with exception of folic acid). By increasing the molarity of the solutions, the binding to the resins of vitamin B12-intrinsic factor complex and of calcium chloride was completely inhibited. In human gastric and duodenal juices, the uptake by the resins of the studied compounds depends on the molarity of the physiological medium tested and partly confirms the results obtained with aqueous solutions. These data obtained in vitro emphasize the necessity of regular monitoring these biochemical parameters during chronic treatment of hypercholesterolaemia conducted with these two resins.

New microporous cholestyramine analog for treatment of hypercholesterolemia.

A new, microporous, uniformly reticulated preparation of cholestyramine is described. The preparation, cholpor, has a higher exchange capacity for chloride than does cholestyramine and swells very little in water. It is 15--20% more potent than chloestyramine in the in vitro binding of sodium cholate; moreover, the binding velocity is considerably higher than that of cholestyramine. Colestipol hydrochloride, also used as a reference anion-exchange resin, is about half as potent as the other two resins; its binding velocity is similar to that of cholpor. Cholpor may be prepared in a suspension form of good palatability. Preliminary clinical findings in short-term trials showed a cholesterol-lowering effect similar to that of cholestyramine with lower doses and fewer side effects.

Binding of bile acids to anion-exchanging drugs in vitro.

Equal amounts of anion exchanger of the drugs, Secholex, Colestipol, Cuemid, and Questran, were incubated at 37 degrees C with human duodenal fluid containing about 7 mM total bile acid. Binding of bile acid to Qestran, which contains about 45% cholestyramine, was fastest: concentration of unbound bile acid after 2 hours was less than 3 mM compared to about 5 mM in the solutions incubated with the other drugs, including Cuemid, which contains about 83% cholestyramine. After 24 hours, differences were less marked, but binding to Qestran was still greatest. Glycocholic acid was least efficiently bound, especially to Secholex and Cuemid. The differences in rates of binding were unaffected by preincubation of the drugs with 1 N HCl to simulate stomach conditions. Although differences between the cholestyramine components of Cuemid and Questran are not ruled out, it is possible that one or more of the other components of Questran significantly affect the in vitro binding of bile acids. Cholestryramine in the form of Questran may be the drug of choice in the treatment of hypercholesterolemia, in which reduction of the bile acid pool is desirable. In cholegenic diarrhoea, however, one of the drugs with lower affinity for glycocholic acid may be preferable.

Preparation of [14C]colestipol hydrochloride and its disposition in the human, dog and rat.

Colestipol hydrochloride, a polymeric, ion-exchange type, hypocholesterolemic agent, acting by sequestering bile acids, was labeled with carbon-14. The disposition of the labeled material was studied in the human, dog and rat. The extent of absorption from the gastrointestinal tract, as judged by urinary excretion of radioactivity, was very small and correlated well with the contents of water-soluble and dialyzable materials in the colestipol hydrochloride. Results were consistent with the dialyzable material in the drug being the absorbable species.