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At least 19 recordsLinked to original sources

PubMed1994

High-performance liquid chromatographic assay for the simultaneous determination of ethyl clofibrate and clofibric acid in plasma. Evaluation of plasma stability of ethyl clofibrate polylactic nanocapsules in human and rat plasmas.

A rapid, sensitive, and selective HPLC assay was developed for the simultaneous determination of ethyl clofibrate and its major metabolite, clofibric acid, in plasma of humans and rats. The assay involves extraction of the compounds into chloroform-isoamyl alcohol (99:1, v/v) from plasma acidified with sulfuric acid. For human plasma, the overall recoveries of ethyl clofibrate and clofibric acid were 63 and 90%, respectively. The limits of detection of the assay for ethyl clofibrate and clofibric acid in human plasma were 1.1 and 1.5 micrograms/ml, respectively. Limits of quantitation of the assay for ethyl clofibrate and clofibric acid in human plasma were 3.6 and 4.9 micrograms/ml, respectively. The HPLC assay was used to monitor the plasma concentration-time profiles of ethyl clofibrate released from polylactic nanocapsules both in man and rat. The simultaneous determination of ethyl clofibrate and clofibric acid provided evidence that these colloidal systems are stable in human plasma whereas they are lysed in rat plasma.

Animals↗

PubMed1993

Further studies on the involvement of selenium in peroxisome proliferation in rat liver. Comparison of effects with clofibric acid and perfluorooctanoic acid and the pharmacokinetics of [14C]clofibrate.

Most effects of the peroxisome proliferator clofibrate on rat liver are marginal or absent in selenium (Se) deficiency. The purpose of the present study was to determine whether the uptake or distribution of clofibrate is altered by Se deficiency. Rats were fed a Se-adequate or -deficient diet for 10-11 weeks and then these same diets with 0.5% (w/w) clofibric acid (the direct acting hydrolysis product of clofibrate) or 0.02% (w/w) perfluorooctanoic acid (PFOA) for 10 days. Other groups of rats received radiolabeled clofibrate by intubation. Clofibric acid was an ineffective as clofibrate in producing effects (i.e. decreased body weight gain, increases in liver somatic index and protein content of the mitochondrial fraction, and increased activities of catalase and peroxisomal fatty acid beta-oxidation) in the liver of Se-deficient rats. Microsomal omega-hydroxylation was, however, equally induced in both dietary groups. In contrast to clofibric acid, the biological effects of PFOA were not affected by Se status. Furthermore, neither the tissue distribution (plasma, liver and kidney) nor the urinary excretion of 14C was affected by Se deficiency. These results demonstrate that the hydrolysis of clofibrate to clofibric acid is not impaired in the Se-deficient rat. In addition, the involvement of Se in the effects of peroxisome proliferators differs for different members of this structurally heterogeneous group of compounds. It is concluded that the Se-deficient rat may provide valuable information concerning the biochemical mechanism(s) underlying peroxisome proliferation.

Animals↗

PubMed1980

[Evaluation of the antilipaemic potential of etofylline clofibrate, its metabolites and clofibrate in dietary-induced hyperlipidaemia in the rat (author's transl)].

Efficacy of 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, ML 1024, Duolip) and its molecule components (metabolites) of structurally similar theophylline esters and of clofibrate as standard was investigated in the artificial hyperlipidaemia of the rat. In accordance with former results etofylline clofibrate was antilipaemically active and, in contrast to similar esters and clofibrate, significantly decreased the cholesterol level. An investigation of the efficacy of its metabolites, either alone or in equivalent mixture, as well as of the standard clofibrate under fat diet demonstrated low efficacy of etofylline, but an increased activity in combination with clofibrate or clofibric acid. The activity of the combination is significantly superior to that of clofibrate under fat diet, but not under normal diet. The increased efficacy of etofylline clofibrate is undoubtedly an unusual potentiation, an additive effect of the metabolites can be excluded. Cholesterol and triglycerides are relevant parameters for the experimental evaluation of the efficacy. Measurement of total lipids offers no additional information. Substitution of triglycerides by total-beta-lipoproteins as parameter seems methodically useful, since values of cholesterol, triglycerides and beta-lipoproteins correlate well under normal diet.

Animals↗

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↗

PubMedDate not supplied

Species differences in the metabolic conjugation of clofibric acid and clofibrate in laboratory animals and man.

The urinary metabolites of single doses of clofibric acid (p-chlorophenoxyisobutyric acid), and its ethyl ester, clofibrate, have been investigated in rat, guinea pig, rabbit, dog, cat, ferret, and human volunteers. Human volunteers, rodents, and rabbits given clofibric acid excreted 60-90% of the 14C dose in the urine in 24 hr, and the only metabolite found was the ester glucuronide of clofibric acid, together with small amounts of the unchanged acid. In the dog, cat, and ferret, however, urinary excretion of 14C was much slower (23-39% of dose in 24 hr) and these species all formed the taurine conjugate of clofibric acid, excreted together with the unchanged acid. The ester glucuronide was found in the urine of dog and ferret but not cat. The fate of clofibrate, the ethyl ester of clofibric acid, in rat, guinea pig, rabbit, and man was similar to that of the parent acid. The characterization of the glucuronic acid and taurine conjugates of clofibric acid is described.

Animals↗

PubMed1980

[Clofibrate therapy in hypercholesterolemia. Reports on medium-long-term movements of HDL- cholesterol by the action of clofibrate].

Clofibrate was administered to 5 selected outpatients suffering from type IIa hyperlipoproteinaemia who had previously undergone dietetic treatment, and one female patient suffering from hypo-HDL-aemia in order to elucidate the question as to whether medium long term clofibrate therapy apart from producing an initial increase relative to the LDL concentration may also lead to an absolute increase in the concentration of HDL cholesterol in serum. According to our findings daily doses of 1 to 2 g clofibrate increase the concentrations of HDL cholesterol and phospholipids within two to four months after therapy was started. These increases remained unchanged within four to eight weeks after having reduced the dose to half its original level. Subsequent HDL cholesterol levels still range above those of the controls prior to clofibrate treatment. After a further clofibrate dose at the original dose level it takes again four to eight weeks until the HDL cholesterol level increases again. Thus, during medium long term therapy the quantitative effect of clofibrate on the lipoprotein pattern is similar to that of bezafibrate and etofibrate. It is only the latency period of an increase in serum concentration of HDL cholesterol that differs: it is longest for clofibrate, shortest for etofibrate, with bezafibrate obviously being right in the middle.

Adult↗

PubMed1980

Changes in the fatty acid composition of the plasma lipid esters during lipid-lowering treatment with diet, clofibrate and niceritrol. Reduction of the proportion of linoleate by clofibrate but not by niceritrol.

The fatty acid composition of the plasma lipid esters has been studied during lipid-lowering treatment of 95 patients with atherosclerotic disease. During the first two months of the trial only a diet was prescribed. During the ensuing two months either clofibrate or niceritrol, a nicotinic acid ester, was added in a randomized order. During the last two months the second drug was added. The combined treatment with diet, clofibrate and niceritrol caused highly significant serum lipid reductions. The fatty acid composition in the plasma lipid esters was determined in samples from each trial period to measure the degree of dietary adherence. During dietary treatment the relative content of saturated and monounsaturated fatty acids secreased and the polyunsaturated fatty acids increased with an increasing ratio between pulyunsaturated and saturated fatty acids (P/S ratio) in the cholesterol esters and triglycerides. Only minor changes were seen in the phospholipids. The changes caused by the diet were partly reversed by clofibrate while niceritrol did not cause any major changes of the fatty acid composition. Clofibrate treatment coincided with increasing amounts of monounsaturated fatty acids, especially oleate (18 : 1), in the cholesterol esters, triglycerides and phospholipids while there were significant reductions of the content of linoleic (18 : 2) acid in both the cholesterol esters and triglycerides. The 18 : 2/18 : 1 ratio decreased significantly in all the lipid esters analyzed. However, the P/S ratio was not significantly affected, partly because the relative content of saturated fatty acids also tended to decrease during clofibrate treatment. It is concluded that addition of clofibrate treatment to patients who are on a diet enriched with polyunsaturated fats is associated with a change from polyunsaturated to monounsaturated fatty acids in the plasma lipid esters but does not significantly effect the ratio between polyunsaturated and saturated fatty acids. The fatty acid changes caused by clofibrate treatment and counteracted by an increased amount of polyunsaturated fat in the diet.

Aged↗

PubMed1986

Separation and measurement of clofibroyl coenzyme A and clofibric acid in rat liver after clofibrate adminstration by reversed-phase high-performance liquid chromatography with photodiode array detection.

A method to identify and quantitate clofibric acid and clofibroyl coenzyme A (CoA) products in rat liver was developed using reversed-phase high-performance liquid chromatography. The system was developed with baseline separation of clofibroyl-CoA from clofibric acid using isocratic elution, with a mobile phase consisting of 52% methanol and 28 mM potassium phosphate buffer (pH 4.2). With this high methanol concentration, the large amount of UV-absorbing materials present in the liver extracts were eluted earlier than the investigated compounds. Clofibroyl-CoA has a characteristic absorbance spectrum with distinct peaks at 260 and 230 nm, while clofibric acid showed only a distinct peak at 230 nm. Using an on-line photodiode array detector, the spectra could be recorded during analysis without interrupting the flow of the mobile phase. This spectral analysis identification possibilities and evaluation of the purity of the chromatographic peaks. In a perchloric extract of rat liver, the recovery of clofibric acid and clofibroyl-CoA added to the liver extract ranged from 70 to 80%. A linear relationship was observed between clofibric acid and clofibroyl-CoA concentration and the area of their peaks in the chromatogram. The detection limit of the method was lower than 5 pmol for both compounds when the absorbance was recorded at 230 nm. The method could be used without modification for the estimation of clofibroyl-CoA and clofibric acid in biological extracts.

Acyl Coenzyme A↗

PubMed2004

Acute and chronic effects of clofibrate and clofibric acid on the enzymes acetylcholinesterase, lactate dehydrogenase and catalase of the mosquitofish, Gambusia holbrooki.

The objective of this study was to investigate both acute and chronic effects of clofibrate and clofibric acid on the enzymes acetylcholinesterase (AChE), lactate dehydrogenase (LDH) and catalase (CAT) of the mosquitofish (Gambusia holbrooki). AChE, commonly used as a biomarker of neurotoxicity, was determined in the total head. LDH, an important enzyme of anaerobic metabolism, was quantified in dorsal muscle, and CAT, enzyme which has been used as indicative parameter of peroxisome proliferation, was determined in the liver. Furthermore, alterations of body and liver weight were also determined, through the calculation of the ratios final body weight/initial body weight, liver weight/final body weight, liver weight/gills weight and liver weight/head weight. Acute exposure of G. holbrooki to both clofibrate and clofibric acid induced a decrease in liver CAT activity, an increase in muscle LDH activity, while no effects were observed on AChE activity. However, chronic exposure did not alter significantly the enzymatic activities, suggesting reduced or null effects over these pathways, relative to effects reported in other species. No effects were observed for the calculated ratios, except a significant weight reduction for males chronically exposed to clofibrate.

Acetylcholinesterase↗

PubMed1983

The analysis of [14C]clofibric acid glucuronide and [14C]clofibric acid in plasma and urine using high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the quantitation of [14C]clofibric acid glucuronide and [14C]clofibric acid using conventional scintillation counting. The assay has a linear relationship between the added and observed ratios of clofibric acid glucuronide: clofibric acid in the range of 0.001-0.6 for plasma and 0.5-100 for urine, and is able to quantitate previously unmeasurable concentrations of clofibric acid glucuronide in plasma.

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↗

PubMed1981

The simultaneous analysis of clofibric acid and probenecid and the direct analysis of clofibric acid glucuronide by high-performance liquid chromatography.

A rapid and selective high-performance liquid chromatographic method for the simultaneous quantitative analysis of clofibric acid and probenecid in plasma and urine and for the direct analysis of clofibric acid glucuronide in plasma is described. Both methods involve direct injection of deproteinised body fluids. Concentrations of as low as 10 mg/l of clofibric acid and probenecid and 1.5 mg/l of clofibric acid glucuronide can be measured by the analysis. The coefficient of variance for these methods ranges from 1--7%.

Chromatography, High Pressure Liquid↗

PubMed2001

Characterization of clofibrate-induced retrograde Golgi membrane movement to the endoplasmic reticulum: clofibrate distinguishes the Golgi from the trans Golgi network.

Clofibrate-induced retrograde Golgi membrane movement was blocked or retarded when NRK cells were treated with sodium azide/2-deoxyglucose, nocodazole, taxol, and destruxin B, indicating that it depends on energy, and the dynamic state of microtubules, and being acidic or vacuolar-type ATPase function. PDMP and phospholipase A2 inhibitors also blocked it. These characteristics are similar to those of brefeldin A (BFA) and nordihydroguaiaretic acid (NDGA), inducers of retrograde Golgi membrane movement. However, clofibrate was distinguished from BFA in that BFA action was insensitive to phospholipase A2 inhibitors and from NDGA in that NDGA stabilized microtubules against nocodazole and its action was almost insensitive to taxol. The trans Golgi network (TGN) was resistant to clofibrate, while BFA and NDGA dispersed it. To our knowledge, clofibrate is the first drug to show such different effects on the Golgi and TGN and, therefore, is expected to be a useful tool to distinguish their architecture and/or membrane dynamics.

Adenosine Triphosphatases↗

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↗

PubMed1980

Simultaneous GLC determination of clofibrate and clofibric acid in human plasma.

A simultaneous assay for the detection of clofibrate and its metabolite, clofibric acid [2-(p-chlorophenoxy)-2-methylpropionic acid], is described. This GLC method is rapid and does not require a derivatization step. It is sensitive to 1-microgram/ml levels of either compound in biological samples and can be used to characterize the in vivo conversion of clofibrate ester to the free acid.

Chromatography, Gas↗

PubMed1993

In vitro phototoxicity of clofibrate. Photochemical and photohemolytic studies on its metabolite clofibric acid.

Aqueous or methanolic solutions of clofibrate and clofibric acid are photolabile towards UVB light under aerobic as well as anaerobic conditions. Nine photoproducts have been identified; their formation involves primary cleavage of the carbon-halogen bond or of the aryloxy-carbon bond, followed by hydrogen abstraction and/or radical recombination. Clofibric acid is phototoxic in vitro as indicated by the photohemolysis test, under both oxygen and argon atmospheres, although the photohemolysis rate is markedly higher under aerobic conditions. Partial inhibition of this process on addition of butylated hydroxyanisole (BHA), reduced glutathione (GSH), sodium azide (NaN3) or 1,4-diazabicyclo[2.2.2]octane (DABCO) suggests the involvement of type I as well as type II mechanisms.

Clofibrate↗

PubMed2000

Different behavior toward racemization in basic media from chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate.

Some chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate, show different configurational stability in basic conditions. Also, extensive racemization occurs when the corresponding optically active acid chlorides are treated with 3 alpha-tropanol, whereas no racemization takes place with 3 alpha-tropanol as hydrochloride salt and with 3 beta-tropanol and 1-methyl-4-hydroxy-piperidine as either the free base or hydrochloride salt. For these aminoalcohols, experimental evidence supports the hypothesis that a ketene intermediate is involved in the racemization process. Formation of intramolecular hydrogen bond is evoked to explain the different ability of aminoalcohols to induce ketene formation and consequent racemization.

Clofibrate↗

PubMed1988

Modification of surfactant metabolizing cells in rat lung by clofibrate, a hypolipidemic peroxisome proliferating agent. Evidence to suggest that clofibrate influences pulmonary surfactant metabolism.

The influence of clofibrate (ethyl-alpha-p-chlorophenoxy-isobutyrate), a hypolipidemic peroxisome proliferating agent, has been tested on the lungs of adult male rats. Drug administration for 7 days caused structural changes in two types of lung cells, both of which are involved in the metabolism of the pulmonary surfactant. By light microscopy the prominent features were the presence of enlarged type II alveolar epithelial cells and foamy intraalveolar macrophages. Compared with controls, type II cells in treated rats apparently contained more numerous surfactant-containing lamellar bodies, as visualized in semi-thin sections of Epon-embedded tissue. This difference was quantified morphometrically by light microscopy: the number of lamellar bodies was estimated as the profile number per individual type II alveolar cell, transsected at its nucleus. Clofibrate administration for 7 days resulted in a significant increase in the number of the lamellar inclusions. In contrast the number of type II alveolar cells per area of lung remained unchanged. There was no evidence of atelectasis or inflammatory infiltration in the drug-treated lungs, a finding confirmed in sections of perfusion-fixed, paraffin-embedded whole lung-lobes. By electron microscopy the lamellar inclusion bodies in the type II alveolar cells in treated rats, apart from being more numerous and sometimes smaller, were morphologically identical to those in controls. The vacuolated alveolar macrophages seen in treated rats also contained various lamellar phospholipid inclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗