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1.
Int J Nanomedicine ; 15: 705-715, 2020.
Article in English | MEDLINE | ID: mdl-32099359

ABSTRACT

BACKGROUND: Bezafibrate is a BCS class II drug as it presents very low solubility in water; therefore, its bioavailability after oral administration is very poor. The aim of this work was to enhance solubility and dissolution rate of bezafibrate in water in order to enhance its oral bioavailability. METHODS: Several formulations were prepared using PVP K30 and Cremophor ELP employing the solvent-evaporation method and the electrospraying technique. Solubility, release rate, bioavailability in male Sprague Dawley rats, and lipid profile attributes in Wistar rats were assessed in comparison with bezafibrate plain powder. Solid-state characterization was carried out using X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). RESULTS: All the formulations exerted positive effect towards the desired goal. In particular, the optimized formulation furnished about 14-fold enhanced solubility and 85.48 ± 10.16% drug was released in 10 min as compared with bezafibrate alone (4.06 ± 2.59%). The drug existed in the amorphous state in the prepared sample as confirmed by XRD and DSC, whilst no drug-excipient interactions were observed through FTIR analysis. Moreover, SEM revealed smooth-surfaced spherical particles of the optimized formulation. A 5.5-fold higher oral bioavailability was achieved with the optimized formulation in comparison with bezafibrate plain powder. Also, TG, LDL and TC were decreased, and HDL was increased considerably in HFD-treated rats. CONCLUSION: The optimized formulation consisting of bezafibrate, PVP K30 and cremophor ELP (1/12/1.5, w/w/w) might be a capable drug delivery system for orally administering poorly water-soluble bezafibrate with improved bioavailability and antihyperlipidemic effects.


Subject(s)
Bezafibrate/pharmacology , Drug Delivery Systems/methods , Hypolipidemic Agents/pharmacology , Nanospheres/chemistry , Polymers/chemistry , Administration, Oral , Animals , Bezafibrate/administration & dosage , Bezafibrate/blood , Bezafibrate/pharmacokinetics , Biological Availability , Calorimetry, Differential Scanning , Hydrophobic and Hydrophilic Interactions , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/blood , Hypolipidemic Agents/pharmacokinetics , Lipids/chemistry , Male , Nanospheres/ultrastructure , Polyethylene Glycols/chemistry , Povidone/chemistry , Powders , Rats, Sprague-Dawley , Solubility , Spectroscopy, Fourier Transform Infrared , X-Ray Diffraction
2.
Intern Med ; 55(18): 2659-61, 2016.
Article in English | MEDLINE | ID: mdl-27629963

ABSTRACT

Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inherited disorder related to recurrent episodes of rhabdomyolysis. The adult myopathic form of CPT II deficiency is relatively benign and difficult to diagnose. The point mutation S113L in CPT2 is very common in Caucasian patients, whereas F383Y is the most common mutation among Japanese patients. We herein present a case of CPT II deficiency in a Japanese patient homozygous for the missense mutation S113L. The patient showed a decreased frequency of rhabdomyolysis recurrence after the administration of a diet containing medium-chain triglyceride oil and supplementation with carnitine and bezafibrate.


Subject(s)
Bezafibrate/therapeutic use , Carnitine O-Palmitoyltransferase/deficiency , Carnitine/therapeutic use , Dietary Supplements , Lipid Metabolism, Inborn Errors/diet therapy , Metabolism, Inborn Errors/diet therapy , Rhabdomyolysis/diagnosis , Asian People , Bezafibrate/blood , Carnitine/blood , Carnitine O-Palmitoyltransferase/blood , Carnitine O-Palmitoyltransferase/genetics , Homozygote , Humans , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/genetics , Male , Metabolism, Inborn Errors/blood , Metabolism, Inborn Errors/genetics , Middle Aged , Point Mutation , Rhabdomyolysis/diet therapy , Rhabdomyolysis/genetics , Treatment Outcome
3.
Eur J Pharm Sci ; 81: 119-28, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26474691

ABSTRACT

A patient with rheumatoid arthritis developed rhabdomyolysis while undergoing treatment with mizoribine concomitantly with bezafibrate. The symptoms rapidly disappeared and laboratory test results normalized when she discontinued the two drugs. The purpose of the present study was to elucidate the transporter-mediated molecular pharmacokinetic mechanisms of drug-drug interactions between bezafibrate and mizoribine. Comparing bezafibrate-mizoribine group with bezafibrate group, the Tmax and Cmax of bezafibrate were essentially unchanged in rats. The AUC of bezafibrate was significantly increased and t1/2ß was prolonged markedly with an obviously reduction in plasma clearance and cumulative urinary excretion. The changes were similar to oral studies following intravenous co-administration. In rat kidney slices, the uptake of bezafibrate was markedly inhibited by p-aminohippurate, benzylpenicillin and probenecid but not by tetraethyl ammonium. Mizoribine not only decreased the uptake of bezafibrate, but also inhibited the uptake of p-aminohippurate and benzylpenicillin. The uptakes of bezafibrate and mizoribine were significantly higher compared to vector-HEK293 cells. The uptakes of bezafibrate and mizoribine in highest concentration were increased 1.63 and 1.46 folds in hOAT1-transfected cells, 1.43 and 1.24 folds in hOAT3-transfected cells, respectively. The Km values of bezafibrate uptake by hOAT1/3hOAT1-/hOAT3-HEK293 K293 cells were increased 1.68 fold in hOAT1-HEK293 cell and 2.12 fold in hOAT3-HEK293 cell in the presence of mizoribine with no change of Vmax. It indicated that mizoribine could inhibit the uptake of bezafibrate by hOAT1/3-HEK293 cells in a competitive way. In conclusion, OAT1 and OAT3 are the target transporters of drug-drug interactions between bezafibrate and mizoribine in pharmacokinetic aspects.


Subject(s)
Bezafibrate/pharmacokinetics , Kidney/metabolism , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Ribonucleosides/pharmacokinetics , Animals , Bezafibrate/blood , Bezafibrate/pharmacology , Bezafibrate/urine , Drug Interactions , HEK293 Cells , Humans , In Vitro Techniques , Kidney/drug effects , Male , Organic Anion Transport Protein 1/genetics , Organic Anion Transporters, Sodium-Independent/genetics , Rats, Wistar , Ribonucleosides/blood , Ribonucleosides/pharmacology
4.
Neurology ; 82(7): 607-13, 2014 Feb 18.
Article in English | MEDLINE | ID: mdl-24453079

ABSTRACT

OBJECTIVE: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. METHODS: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise. RESULTS: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise. CONCLUSION: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates in disorders of FAO do not translate into clinically meaningful effects in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.


Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Bezafibrate/pharmacology , Carnitine O-Palmitoyltransferase/deficiency , Fatty Acids/metabolism , Hypolipidemic Agents/pharmacology , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/metabolism , Mitochondrial Diseases/drug therapy , Mitochondrial Diseases/metabolism , Muscle, Skeletal/metabolism , Muscular Diseases/drug therapy , Muscular Diseases/metabolism , Acyl-CoA Dehydrogenase, Long-Chain/blood , Acyl-CoA Dehydrogenase, Long-Chain/metabolism , Adolescent , Adult , Aged , Bezafibrate/administration & dosage , Bezafibrate/blood , Clinical Protocols , Congenital Bone Marrow Failure Syndromes , Cross-Over Studies , Fatty Acids/blood , Female , Humans , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/blood , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/diagnosis , Male , Middle Aged , Mitochondrial Diseases/blood , Mitochondrial Diseases/diagnosis , Muscle, Skeletal/drug effects , Muscular Diseases/blood , Muscular Diseases/diagnosis , Treatment Outcome , Young Adult
5.
Bioorg Med Chem Lett ; 22(20): 6425-8, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22975299

ABSTRACT

Three water-soluble fibrates (fenofibrate, bezafibrate and chlofibrate) conjugated with a symmetrically branched glyceryl trimer (BGL003) were synthesized, and an evaluation of the fenofibrate-BGL003 conjugate as a candidate for anti-hyperlipemia drug was carried out using rats. The water-solubility of the fenofibrate-BGL003 conjugate was several thousand times greater than that of the original fenofibrate. The lipid-lowering effects of the fenofibrate-BGL003 conjugate were as strong as those of the same grams of fenofibrate. The actual active species of fenofibrate, fenofibric acid, was detected in rats' blood, but neither the fenofibrate-BGL003 conjugate nor fenofibrate was detected, probably due to enzymatic hydrolysis of the ester bond. The plasma concentration of fenofibric acid derived from the fenofibrate-BGL003 conjugate was five times higher than that derived from fenofibrate 4h after administration.


Subject(s)
Bezafibrate/chemistry , Clofibrate/chemistry , Fenofibrate/chemistry , Hypolipidemic Agents/chemistry , Animals , Bezafibrate/blood , Bezafibrate/chemical synthesis , Bezafibrate/pharmacology , Clofibrate/blood , Clofibrate/chemical synthesis , Clofibrate/pharmacology , Fenofibrate/blood , Fenofibrate/chemical synthesis , Fenofibrate/pharmacology , Hypolipidemic Agents/blood , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/pharmacology , Male , Rats , Rats, Sprague-Dawley , Solubility , Triglycerides/blood , Water/chemistry
6.
Anal Biochem ; 427(2): 187-9, 2012 Aug 15.
Article in English | MEDLINE | ID: mdl-22613053

ABSTRACT

In vitro cell-based reporter assays are a useful tool for the discovery and characterization of nuclear receptor modulators. However, the properties of a given molecule can differ when tested in vitro and in vivo as a result of the molecule's bioavailability. In this work, we describe a methodology that allows the detection of the PPARγ (peroxisome proliferator-activated receptor gamma) agonist bezafibrate in rat serum by an in vitro cell-based reporter assay. This methodology could be adapted to the detection and characterization of bioavailable PPARγ or other nuclear receptor modulators in serum, extending the possibilities of the classical in vitro assays.


Subject(s)
Bezafibrate/blood , Hypolipidemic Agents/blood , Luciferases, Renilla/analysis , Mutant Chimeric Proteins/agonists , PPAR gamma/agonists , Animals , Bezafibrate/pharmacokinetics , Biological Availability , Genes, Reporter , HeLa Cells , Humans , Hypolipidemic Agents/pharmacokinetics , Ligands , Mutant Chimeric Proteins/genetics , Mutant Chimeric Proteins/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Plasmids , Rats , Rats, Wistar , Transfection
7.
J Chromatogr Sci ; 48(5): 362-6, 2010.
Article in English | MEDLINE | ID: mdl-20515529

ABSTRACT

An isocratic high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of bezafibrate in biological fluids. Bezafibrate was separated on a C(18) analytical column (150 x 4.6 mm i.d., 5 microm particle size) with 0.01 M phosphate buffer (pH 3.5)-acetonitrile-methanol (50:40:10) as mobile phase at a flow rate of 1.0 mL/min. The UV detector was set to 230 nm. Bezafibrate was extracted from human plasma using a simple liquid-liquid extraction with tert-butyl methyl ether. Parameters such as linearity, precision, accuracy, recovery, specificity, and stability were evaluated by method validation studies. All the parameters remained within acceptable limits. The validated procedure was linear in the concentration range of 0.2-50 microg/mL. The proposed method used for individual drug determinations is applicable for therapeutic monitoring purposes as well as for use in pharmacokinetic investigations. As an example, the practical quantification limit for bezafibrate in plasma was about 0.05 microg/mL with precision of 10.2% and accuracy of 112.6%. The method was applied in a study of the pharmacokinetics of bezafibrate in six healthy volunteers, who ingested a single oral dose of 200 mg.


Subject(s)
Bezafibrate/blood , Chromatography, High Pressure Liquid/methods , Hypolipidemic Agents/blood , Bezafibrate/pharmacokinetics , Humans , Hypolipidemic Agents/pharmacokinetics
8.
J Chromatogr Sci ; 46(10): 844-7, 2008.
Article in English | MEDLINE | ID: mdl-19007489

ABSTRACT

A sensitive and selective high-performance liquid chromatographic-UV (HPLC-UV) method for the determination of bezafibrate in human plasma has been developed. Sample treatment was based on protein precipitation with a perchloric acid-methanol solution 10:90 (v/v). Analytical determination was carried out by HPLC with UV detection at 235 nm. Chromatographic separation was achieved on a C18 column by isocratic elution with acetonitrile-ammonium acetate aqueous solution (10 mmol/L; pH 4.0) (44:56, v/v) at a flow rate of 1.0 mL/min. The method was linear in the concentration range of 0.1-15.0 microg/mL. The lower limit of quantitation was 0.1 microg/mL. The intra-and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 6.96%. The accuracy determined at three concentrations (0.2, 2.0, and 10.0 microg/mL for bezafibrate) was within +/- 10.0% in terms of accuracy. The method was successfully applied for the evaluation of pharmacokinetic profiles of bezafibrate dispersible tablet in 20 healthy volunteers. The results show that AUC, C(max), and T(1/2) between the testing formulation and reference formulation have no significant difference (P > 0.05). Relative bioavailability was 105.0 +/- 15.7%.


Subject(s)
Bezafibrate/blood , Bezafibrate/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Bezafibrate/chemistry , Humans , Hypolipidemic Agents/blood , Hypolipidemic Agents/pharmacokinetics , Molecular Structure , Reproducibility of Results , Spectrophotometry, Ultraviolet , Tablets
9.
Clin Pharmacol Ther ; 69(5): 340-5, 2001 May.
Article in English | MEDLINE | ID: mdl-11372002

ABSTRACT

BACKGROUND: Concomitant use of fibrates with statins has been associated with an increased risk of myopathy, but the underlying mechanism of this adverse reaction remains unclear. Our aim was to study the effects of bezafibrate and gemfibrozil on the pharmacokinetics of lovastatin. METHODS: This was a randomized, double-blind, 3-phase crossover study. Eleven healthy volunteers took 400 mg/day bezafibrate, 1200 mg/day gemfibrozil, or placebo for 3 days. On day 3, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, gemfibrozil, and bezafibrate were measured up to 24 hours. RESULTS: Gemfibrozil markedly increased the plasma concentrations of lovastatin acid, without affecting those of the parent lovastatin compared with placebo. During the gemfibrozil phase, the mean area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of lovastatin acid was 280% (range, 131% to 1184%; P < .001) and the peak plasma concentration (Cmax) was 280% (range, 123% to 1042%; P < .05) of the corresponding value during the placebo phase. Bezafibrate had no statistically significant effect on the AUC(0-24) or Cmax of lovastatin or lovastatin acid compared with placebo. CONCLUSIONS: Gemfibrozil markedly increases plasma concentrations of lovastatin acid, but bezafibrate does not. The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partially of a pharmacokinetic origin. The risk of developing myopathy during concomitant therapy with lovastatin and a fibrate may be smaller with bezafibrate than with gemfibrozil.


Subject(s)
Bezafibrate/pharmacology , Gemfibrozil/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hypolipidemic Agents/pharmacology , Lovastatin/pharmacokinetics , Adult , Area Under Curve , Bezafibrate/blood , Cross-Over Studies , Drug Interactions , Female , Gemfibrozil/blood , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Hypolipidemic Agents/blood , Lovastatin/blood , Male
10.
Jpn Circ J ; 63(6): 471-7, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10406588

ABSTRACT

Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p<0.01) in the bezafibrate-treated group, but a significant (p<0.05) reduction in HDL-C was observed in both the Ch + probucol (group 3) and Ch + probucol plus bezafibrate (group 5) groups; no significant difference was observed between groups 3 and 5. Significant correlation (p<0.01) was found between serum low density lipoprotein cholesterol (LDL-C) levels and plasma probucol concentrations in groups 3 and 5, but no correlation was found between plasma concentrations of probucol/bezafibrate and serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma fraction increased in the Ch-, Ch + probucol-, and Ch + probucol and bezafibrate-fed groups (groups 2, 3 and 5, respectively), whereas a significant reduction in this activity was observed in the Ch + bezafibrate-fed group (group 4). An analysis of covariance showed that the CETP activity responded more sensitively to drug treatment than did the serum HDL-C level. CETP mRNA in liver tissue was assessed by Northern blotting at 8 weeks, but no changes were observed among the 5 groups. Probucol decreased and bezafibrate increased serum HDL-C levels, through CETP activity without affecting liver CETP mRNA levels, and the decrease in HDL-C levels produced by probucol could not be reversed by bezafibrate.


Subject(s)
Anticholesteremic Agents/pharmacology , Bezafibrate/pharmacology , Carrier Proteins/genetics , Cholesterol Esters/genetics , Glycoproteins , Hypolipidemic Agents/pharmacology , Lipoproteins/metabolism , Probucol/pharmacology , RNA, Messenger/analysis , Animals , Anticholesteremic Agents/blood , Base Sequence , Bezafibrate/blood , Blotting, Northern , Carrier Proteins/analysis , Carrier Proteins/blood , Cholesterol/blood , Cholesterol Ester Transfer Proteins , Cholesterol Esters/analysis , Cholesterol Esters/blood , Cholesterol, HDL/blood , Chromatography, High Pressure Liquid , Hypolipidemic Agents/blood , Lipids/blood , Lipoproteins/blood , Liver/chemistry , Liver/drug effects , Male , Molecular Sequence Data , Probucol/blood , Rabbits , Reverse Transcriptase Polymerase Chain Reaction
11.
Farmaco ; 53(10-11): 690-2, 1998.
Article in English | MEDLINE | ID: mdl-10205855

ABSTRACT

In the present study, the bezafibrate levels were measured in serum of rats treated with lead nitrate using a high performance liquid chromatography (HPLC) method. The results have shown that the peak corresponding to bezafibrate in the chromatogram is reduced in serum of rats treated with bezafibrate plus lead, indicating that lead treatment accelerates the metabolism of bezafibrate in rats.


Subject(s)
Bezafibrate/blood , Hypolipidemic Agents/blood , Lead/pharmacology , Mitogens/pharmacology , Nitrates/pharmacology , Administration, Oral , Animals , Bezafibrate/metabolism , Chromatography, High Pressure Liquid , Drug Interactions , Hypolipidemic Agents/metabolism , Injections, Intravenous , Male , Rats , Rats, Wistar
13.
J Chromatogr B Biomed Appl ; 687(2): 437-42, 1996 Dec 13.
Article in English | MEDLINE | ID: mdl-9017468

ABSTRACT

A selective high-performance liquid chromatographic method to assess either bezafibrate, ciprofibrate or fenofibric acid plasma levels is described. Drugs are extracted with diethyl ether, after acidification with HCL. An isocratic acetonitrile 0.02 M H3PO4 (55:45) mobile phase, a C18 microns) column and UV detection are used. The LOQ found was 0.25 microgram/ml for the three fibrates. Intra- and inter-assay accuracy ranges were 90-107% and 82-111%: 96-115% and 94-107%: 94-114% and 94-126% for bezafibrate, ciprofibrate and fenofibric acid, respectively. Intra- and inter-assay precision (C.V.% ranges) were 1.72-3.06% and 2.66-7.67%: 1.88-4.64% and 0.62-2.99%: 1.26-4.69% and 3.56-7.17% for the three fibrates studied. Its sensitivity, accuracy and precision make it a useful tool for monitoring plasma levels of these drugs in a clinical setting and for research purposes.


Subject(s)
Bezafibrate/blood , Chromatography, High Pressure Liquid/methods , Clofibric Acid/analogs & derivatives , Fenofibrate/analogs & derivatives , Hypolipidemic Agents/blood , Calibration , Clofibric Acid/blood , Fenofibrate/blood , Fibric Acids , Humans , Reproducibility of Results , Sensitivity and Specificity
14.
Br J Clin Pharmacol ; 41(5): 381-7, 1996 May.
Article in English | MEDLINE | ID: mdl-8735678

ABSTRACT

1. We have examined the interaction between aerobic exercise and lipid-lowering drugs in a crossover study of 16 healthy normolipidaemic volunteers who each received 21 days' treatment with bezafibrate (400 mg), fluvastatin (40 mg), and placebo, in random order. 2. Fluvastatin treatment reduced pre-exercise total cholesterol (TC) by 23% (P < 0.0001), low-density lipoprotein cholesterol (LDL-C) by 33% (P < 0.0001), and plasma triglycerides by 11%, compared with pre-treatment values. Bezafibrate reduced TC by 11% (P < 0.01); LDL-C by 9%; and plasma triglycerides by 40% (P < 0.01), compared with pre-treatment values. 3. During exercise, in comparison with placebo, and fluvastatin treatment, respectively, bezafibrate significantly reduced mean fat oxidation: 31% vs 39%, P = 0.035, 31% vs 39%, P = 0.002, plasma free fatty acid (FFA) availability, e.g. after 90 min of exercise: (t90) 520 vs 662 mumol 1(-1), P = 0.054, 520 vs 725 mumol 1(-1), P = 0.016, and plasma levels of glycerol (t90): 59 vs 74 mumol 1(-1), P = 0.037, 59 vs 73 mumol 1(-1), P = 0.016. Fluvastatin had no impact on fat metabolism in comparison with placebo. 4. Reduced plasma FFA concentration and lower fat oxidation during prolonged exercise on bezafibrate treatment may be due to an inhibition of hepatic acetyl coenzyme A carboxylase, resulting in reduced FFA release from adipose tissue. 5. The possibility that impaired fat metabolism on fibrates could induce premature fatigue during exercise of moderate duration and intensity should be examined in hyperlipidaemic patients.


Subject(s)
Bezafibrate/pharmacology , Exercise/physiology , Fatty Acids, Monounsaturated/pharmacology , Fatty Acids, Nonesterified/metabolism , Hydroxymethylglutaryl CoA Reductases/pharmacology , Hypolipidemic Agents/pharmacology , Indoles/pharmacology , Adult , Analysis of Variance , Bezafibrate/blood , Cross-Over Studies , Double-Blind Method , Energy Metabolism/drug effects , Fatty Acids, Monounsaturated/blood , Female , Fluvastatin , Humans , Hydroxymethylglutaryl CoA Reductases/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypolipidemic Agents/blood , Indoles/blood , Male , Oxidation-Reduction
15.
Int J Clin Pharmacol Res ; 7(2): 149-55, 1987.
Article in English | MEDLINE | ID: mdl-3583496

ABSTRACT

In this study the pharmacokinetics of a new slow-release formulation of bezafibrate (a hypolipaemic drug) were evaluated in a group of six healthy volunteers. In the first part of the study the bioavailability of this formulation was compared to the normal preparation of bezafibrate. In the second part of the experiment the possible accumulation was studied. The subjects were administered the slow-release preparation at 08h00 for seven consecutive days. The resulting data indicate that the slow-release formulation shows a lower dispersion of Tmax values. There was an increase of the plasma half-life from 1.9 to 5.5 h, but a possibility of accumulation could be excluded.


Subject(s)
Bezafibrate/administration & dosage , Adult , Bezafibrate/blood , Bezafibrate/urine , Biological Availability , Delayed-Action Preparations , Half-Life , Humans , Kinetics , Male
16.
Klin Wochenschr ; 64(19): 910-6, 1986 Oct 01.
Article in English | MEDLINE | ID: mdl-3784441

ABSTRACT

Hyperlipidaemia may contribute to the high rate of cardiovascular complications in patients on chronic haemodialysis (CHD). However, possibilities of lipid lowering therapy in CHD are still limited. The applicability of bezafibrate (BF), a recently developed clofibrate analogue, was investigated in patients on CHD with triglyceride and/or total cholesterol levels above 300 mg/dl. The lipid lowering effect was studied in a placebo-controlled trial over 6 months in 19 patients. Long-term effect was followed in six patients over a mean period of 29 months. Elimination half-life and mean therapeutic serum concentration were calculated by 72-h BF serum profiles, obtained after the first drug administration of a single 200-mg dose and during steady state after 12 weeks of treatment. Elimination half-lives were 17 h at start and 22 h after 12 weeks compared with 2 h in subjects with normal renal function. Dose reduction to 200 mg every 3rd day was necessary and resulted in a mean therapeutic serum concentration of 3.4 mg/l, which was similar to 3.0 mg/l of normal subjects, who received the dose optimal for lowering of lipids (200 mg 3 X/day). The protein-bound serum fraction of BF was decreased to 8% in CHD patients, compared with 95% found in normal subjects. BF therapy resulted in a marked reduction of serum triglycerides from 478 mg/dl by 31% and total cholesterol levels from 311 mg/dl by 19% as well as beta-Lp-cholesterol from 178 mg/dl by 17%, whereas the initially low alpha-Lp-cholesterol increased significantly from 18.3 mg/dl by 58%.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Bezafibrate/therapeutic use , Coronary Disease/drug therapy , Hyperlipoproteinemia Type IV/drug therapy , Kidney Failure, Chronic/blood , Renal Dialysis , Administration, Oral , Adult , Aged , Bezafibrate/adverse effects , Bezafibrate/blood , Cholesterol/blood , Coronary Disease/blood , Female , Half-Life , Humans , Hyperlipoproteinemia Type IV/blood , Male , Metabolic Clearance Rate , Middle Aged , Triglycerides/blood
17.
J Chromatogr ; 344: 259-65, 1985 Nov 08.
Article in English | MEDLINE | ID: mdl-4086546

ABSTRACT

A selective and time-saving high-performance liquid chromatographic method to assess bezafibrate plasma and urine levels is described. Bezafibrate is extracted from plasma matrix using diethyl ether, after acidification with hydrochloric acid. The urine samples are directly analysed, after dilution with the mobile phase. The method is used to assess bezafibrate plasma and urine levels in man, after administration of therapeutic doses of bezafibrate. The results obtained are in agreement with previously published data.


Subject(s)
Bezafibrate/analysis , Bezafibrate/blood , Bezafibrate/urine , Chromatography, High Pressure Liquid , Drug Stability , Humans
18.
Pharmatherapeutica ; 4(5): 267-77, 1985.
Article in English | MEDLINE | ID: mdl-4070320

ABSTRACT

Diurnal lipid and lipoprotein profiles were measured in 28 healthy volunteers after 10-day treatment periods with placebo, bezafibrate (200 mg 3-times daily) or clofibrate (500 mg 3-times daily) in a double-blind, parallel trial. The two drugs lowered fasting triglyceride and cholesterol levels (p less than or equal to 0.05 for cholesterol with bezafibrate vs placebo). Diurnal triglyceride profiles were lowest with bezafibrate due to lowest fasting triglycerides. Alimentary lipaemia with placebo was mild and due to increased VLDL-triglycerides, while the other lipoprotein lipids and total plasma cholesterol remained virtually unchanged during the day. Bezafibrate (half-life 2 hours) and clofibrate (half-life 15 hours) gave similar diurnal triglyceride patterns. The diurnal values were dependent on the fasting values. Changes in the cholesterol/phospholipid ratio during the day may be related to altered post-prandial composition of HDL.


Subject(s)
Bezafibrate/pharmacology , Clofibrate/pharmacology , Lipids/blood , Lipoproteins/blood , Adult , Bezafibrate/blood , Cholesterol/blood , Circadian Rhythm , Clofibrate/blood , Half-Life , Humans , Male , Triglycerides/blood
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