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At least 19 recordsLinked to original sources
PubMed1977

Clofibrate and clofibric acid: comparison of the metabolic disposition in rats and dogs.

In rats, equimolar oral doses of [14C]clofibrate and [14c]clofibric acid produced essentially the same profiles of blood levels, tissue distribution and excretion of radioactivity. Both compounds were completely absorbed, and all radioactivity found in the serum was due to clofibric acid (CPIB). Tissues contained readily detectable radioactivity levels, but the concentration was generally lower than in serum. A large proportion of CPIB in liver, heart, kidney, fat and muscle was associated with intracellular space. In rat urine, CPIB was present both free and conjugated with glucuronic acid. Approximately 97% of the serum CPIB was not conjugated. Identical decreases in serum lipids and hepatic cholesterol synthesis were observed in rats treated for 1 week with either compound. In dogs, the serum contained 40% more radioactivity after [14C]clofibric acid than after an equimolar oral dose of [14C]clofibrate; approximately 88% of the serum radioactivity was due to CPIB. Some biliary excretion was detected. The extent of binding to serum protein varied with concentration of CPIB and with the species; the affinity was in the order man greater than dog greater than rat. The results demonstrate that clofibric acid and clofibrate are metabolically and pharmacologically equivalent in rats, but not in dogs. The data are in accordance with the view that the pharmacological activity of clofibrate is due to clofibric acid.

Animals↗
PubMed1977

Plasma clofibric acid (CPIB) levels induced by three marketed compounds releasing clofibric acid, in volunteers.

The very low plasma clofibric acid levels achieved in normolipemic volunteers during 96 h by a single dose of alufibrate (basic aluminum salt of clofibric acid) as 4 x 360 mg tablets, have been confirmed. With a crossover study in healthy volunteers receiving therapeutic doses of clofibrate as 2x500 mg capsules, clofibride as 2x450 mg capsules, twice daily for ten days, the plasma clofibric acid concentrations were already found in the therapeutic range after two days and remained above 80 mug/ml at the tenth day. On the other hand, the plasma clofibric acid concentrations measured during a ten-day administration of alufibrate as 2x360 mg tablets twice daily, were regularly found to be much lower at each time; they did not reach levels exceeding 60 mug/ml.

Adult↗
PubMed1978

[Comparison between combination therapy with clofibrate and beta-pyridylcarbinol and clofibrate monotherapy (author's transl].

In order to determine whether the lipid-lowering effect of combined treatment with clofibrate and beta-Pyridylcarbinol exceeds that of clofibrate monotherapy, a double-blind crossover study was performed. 17 patients with primary hyperlipoproteinemia of Type IIa and 10 patients with primary hyperlipoproteinemia of Type IIb received either Lipofacton (1.000 mg clofibrate and 50 mg beta-pyridylcarbinol per day) or clofibrate (1.500 mg per day) for a period of 6 weeks each. Before beginning therapy and between both periods of medication, placebo was administered for 14 days. In both total plasma and in the LDL fraction the cholesterol level was lowered by less than 10% for both substances. In patients with hyperlipoproteinemia of Type IIb, the triglyceride levels were lowered by about 40%.

Adolescent↗
PubMed1977

Comparison of the lipid-lowering effect of clofibrate, and of clofibrate plus beta-pyridylcarbinol.

Forty-eight patients under 65 years were included in a double blind study comparing the lipid-lowering effect of clofibrate with that of beta-pyridylcarbinol combined with clofibrate. Over 4 months there was no significant difference in the lipid-lowering effect of either regime. A mean reduction of triglyceride of approximately 30% and of cholesterol of 18% was observed. Both drugs caused significantly greater reductions than placebo. No serious side-effects were noted.

Analysis of Variance↗
PubMed1979

Long-term effect of the combination of calcium clofibrate and calcium carbonate on serum total cholesterol, triglyceride and high density lipoprotein--cholesterol concentrations in hyperlipoproteinaemia. A comparative study with clofibrate.

Thirty hyperlipidaemic patients (19 with type IIA, 4 with IIB and 7 with type IV hyperlipoproteinaemia) were subjected to therapy with calcium clofibrate and calcium carbonate (4C, 2 + 2 g/day for 6 months) and the effect was compared with clofibrate (1C, 2 g/day) which was given for 6 months as well, in a single-blind placebo-controlled study. 4C and 1C decreased total serum cholesterol levels especially in subgroups IIA and IIB. 4C was somewhat more effective than 1C in decreasing (VLDL + LDL)-cholesterol in subgroup IIA. The HDL-cholesterol concentrations and the ratio of HDL-cholesterol and total cholesterol increased during treatment with both 1C and 4C. The HDL-cholesterol increase (vs. placebo) was 18%. The concentrations of serum triglycerides decreased by 33% during both treatment periods and there was no significant difference between 1C and 4C.

Adult↗
PubMedDate not supplied

Measurement of clofibric acid (CPIB) metabolites in plasma of patients on clofibrate therapy.

1. The metabolites of clofibric acid [CPIB;2-(chlorophenoxy)-2-methylpropionic acid] are present in the plasma of patients on clofibrate therapy. The highest plasma concentrations of CPIB in metabolite form (up to 51 micrograms/ml) were generally found in patients with renal disease. Negligible concentrations (less than or equal to 2 micrograms/ml) were found in only seven patients out of thirty-six studied. 2. The two conjugates of CPIB found in urine were present in plasma. 3. When measuring conjugated CPIB in plasma it is essential to take care in the handling and storage of specimens, and to select an assay method known to be specific for unmetabolized CPIB.

Clofibrate↗
PubMedDate not supplied

Separation of two conjugates of clofibric acid (CPIB) found in the urine of subjects taking clofibrate.

1. Two main conjugates of CPIB (2-[chlorophenoxy]-2-methylpropionic acid) are present in the urine of subjects taking clofibrate. The metabolites can be separated by thin-layer chromatography (TLC). 2. Both conjugates are hydrolysed by dilute alkali, but only one is hydrolysed by the enzyme beta-glucuronidase. In eighty-five urine specimens this conjugate accounted for an average of 54.5% (range 25-70%) of the total CPIB, while 2.6-12.45% (mean 5.1%) was present as free CPIB.

Chromatography, Gas↗
PubMed1992

Fat intake and clofibrate administration have interrelated effects on liver cholesterol concentration and serum butyryl cholinesterase activity in rats.

Rats were fed for 15 d purified diets with different amounts of coconut fat, and with or without clofibrate. Fat was added at the expense of an isoenergetic amount of glucose. The hypolipidemic action of clofibrate was not influenced by the amount of fat in the diet. Clofibrate did not affect liver cholesterol concentration in rats fed the low fat diet, but it counteracted the rise in liver cholesterol seen in rats fed the high fat diet. This could relate to the observed raised intestinal clofibrate-hydrolyzing activity of rats fed the high fat diet, because hydrolysis of clofibrate gives rise to its biologically active form. In rats fed the low fat diet, but not in those fed the high fat diet, clofibrate raised the activity of serum esterase-1, which (unlike esterase-2) does not hydrolyze clofibrate. Possibly, the dramatic stimulatory effect of fat feeding on serum esterase-1 activity had overruled any influence of clofibrate. Clofibrate elevated serum butyryl cholinesterase activity, with this effect being amplified by fat feeding. High levels of dietary fat in the absence of dietary clofibrate did not alter serum butyryl cholinesterase activity. Clofibrate did not change butyryl cholinesterase and esterase-1 activities in small intestine. The high fat diet caused slightly higher levels of butyryl cholinesterase activity in small intestine, but markedly raised intestinal esterase-1 activity. This study shows that certain effects of clofibrate and a high fat diet are interrelated.

Animals↗
PubMed1991

In vivo covalent binding of clofibric acid to human plasma proteins and rat liver proteins.

Recent studies have shown that acyl-glucuronide conjugates are chemically reactive electrophilic metabolites that can undergo transacylation reactions resulting in intra-molecular rearrangement, hydrolysis and covalent binding of aglycone to albumin both in vitro and in vivo. The hypolipidaemic agent clofibrate is eliminated almost entirely as clofibric acid glucuronide in humans and rats. The formation of clofibric acid-protein adducts was investigated in 14 patients receiving 0.5-2.0 g/day of clofibrate for hypercholesterolaemia, and in liver homogenates from 20 rats administered 280 mg/kg/day of clofibric acid for up to 21 days. Total clofibric acid concentrations in the patients ranged from 0 to 114 mg/L. Covalently bound clofibric acid-protein adducts were detected in all patients, even in one subject in whom there was no measurable plasma clofibric acid. Concentrations ranged from 2.2 to 53.4 ng/mg protein and, in eight patients receiving 1.0 g/day of clofibrate, were correlated (P less than 0.05) with renal function as assessed by creatinine clearance. Clofibric acid-protein adducts were also present in rat liver homogenates, and increased with increasing duration of treatment (P less than 0.0001), from a mean (SE) of 10.1 (0.7) to 32.3 (1.6) ng/mg protein. The covalent binding of drugs to tissue macromolecules has traditionally been associated with toxicity. Further research is required to elucidate the role of acyl-glucuronide conjugates in the formation of drug-protein adducts and their biological consequences.

Animals↗
PubMedDate not supplied

Lifetime prolongation in voluntary alcohol-consuming rats (SHR) treated with clofibrate.

Clofibrate affects lipid and alcohol as well as drug and eicosanoid metabolism. Spontaneous hypertensive rats (SHR) further increase their high voluntary alcohol consumption during clofibrate feeding. The interaction of alcohol and clofibrate was studied in two long-term trials. Seventy-nine male SHR (aged 27 weeks) were offered increasing concentrations of ethanol, up to 30% (tap water ad lib), and 3 months later 0.5% clofibrate-food. Four groups were established: N, normal controls; NA, standard diet+alcohol; C, clofibrate feeding; and CA, clofibrate feeding + alcohol. Food intake, alcohol consumption, body weight, and laboratory values were recorded continuously. Life duration (weeks) after the start of the trial was 63.3 +/- 3.3 in N, 73 +/- 2.6 in NA, 77.7 +/- 4.3 in C, and 90.3 +/- 2.8 in CA. There were no alcohol-related liver findings in NA and CA. Most of the animals died of cardiac and renal failure. An increase of tumors in clofibrate-treated rats was not observed. Voluntary alcohol consumption or clofibrate feeding significantly lengthens lifetime, which is prolonged by 42% if ethanol is combined with clofibrate. This is obviously not mediated by the lipid lowering effect or an influence on body weight and blood pressure of either clofibrate or alcohol.

Alcohol Drinking↗
PubMed1992

Effects of clofibric acid on the activity and activity state of the hepatic branched-chain 2-oxo acid dehydrogenase complex.

Feeding clofibric acid to rats caused little or no change in total activity of the liver branched-chain 2-oxo acid dehydrogenase complex (BCODC). No change in mass of liver BCODC was detected by immunoblot analysis in response to dietary clofibric acid. No changes in abundance of mRNAs for the BCODC E1 alpha, E1 beta and E2 subunits were detected by Northern-blot analysis. Likewise, dietary clofibric acid had no effect on the activity state of liver BCODC (percentage of enzyme in the dephosphorylated, active, form) of rats fed on a chow diet. However, dietary clofibric acid greatly increased the activity state of liver BCODC of rats fed on a diet deficient in protein. No stable change in liver BCODC kinase activity was found in response to clofibric acid in either chow-fed or low-protein-fed rats. Clofibric acid had a biphasic effect on flux through BCODC in hepatocytes prepared from low-protein-fed rats. Stimulation of BCODC flux at low concentrations was due to clofibric acid inhibition of BCODC kinase, which in turn allowed activation of BCODC by BCODC phosphatase. Inhibition of BCODC flux at high concentrations was due to direct inhibition of BCODC by clofibric acid. The results suggest that the effects of clofibric acid in vivo on branched-chain amino acid metabolism can be explained by the inhibitory effects of this drug on BCODC kinase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗