Cessation of Bezafibrate in patients with chronic kidney disease improves renal function.

Bezafibrate (BzF) is eliminated by renal excretion and dosage must be reduced in patients with chronic kidney disease (CKD). There is a concern that BzF causes a further deterioration in renal function in patients with CKD. This study assessed whether BzF discontinuation or dose reduction in CKD patients improves renal function. 117 CKD patients treated with BzF between 2009 and 2014 were studied for demographics, comorbid conditions and laboratory variables. Data compared 2 groups: an intervention group of 64 patients where recommendations regarding BzF administration was implemented and a control group of 37 patients. Follow-up was maintained for 12 months. In the intervention group, estimated glomerular filtration rate (eGFR) increased from 38 to 42 mL/min/1.73 m2 (p = 0.01); blood urea levels decreased from 81 to 77 mg/dL (p = 0.04). Serum creatinine decreased by more than 0.2 mg/dL in 45% of the intervention group, as compared to 19% of the control group (p < 0.01). Improvement in eGFR was seen exclusively in patients who stopped BzF completely (eGFR increased from 38 to 44 mL/min/1.73 m2). In the intervention group, TG level increased from 183 to 220 mg/dL (p < 0.001). BzF cessation in approximately 50% of patients with CKD was associated with an increase in eGFR.

Electrosprayed Polymeric Nanospheres for Enhanced Solubility, Dissolution Rate, Oral Bioavailability and Antihyperlipidemic Activity of Bezafibrate.

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.

Temperature-Induced Surface Effects on Drug Nanosuspensions.

PURPOSE: The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods. METHODS: Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. RESULTS: It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles. CONCLUSIONS: The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.

Bezafibrate-mizoribine interaction: Involvement of organic anion transporters OAT1 and OAT3 in rats.

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.

Detection of bioavailable peroxisome proliferator-activated receptor gamma modulators by a cell-based luciferase reporter system.

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.

Exposure to human pharmaceuticals Carbamazepine, Ibuprofen and Bezafibrate causes molecular effects in Dreissena polymorpha.

Carbamazepine (CBZ), Ibuprofen (IBU) and Bezafibrate (BEZ) were tested for their potential to bioaccumulate and provoke molecular changes in the non-target organism Dreissena polymorpha. mRNA changes of enzymes and other proteins involved in the prevention from protein damage (heat shock protein 70, hsp70) and oxidative stress (superoxide dismutase, SOD; catalase, CAT; metallothionein, MT), biotransformation (pi-class glutathione S-transferase, piGST; aryl hydrocarbon receptor, AH-R), elimination (P-glycoprotein, P-gp) and reversible protein posttranslational modification (protein phosphatase 2A, PP2A) served as molecular biomarkers. Mussels were exposed in a flow-through system to increasing concentrations of the three substances (1, 10, 100 and 1000 nM). The two lower concentrations correspond to environmentally relevant concentrations detected in surface and effluent waters, respectively. Measuring tissue concentration after one, four and seven days the uptake of CBZ and IBU by the mussels could be evidenced, whereas no accumulation data could be achieved for BEZ. The bioconcentration factor was highest for mussels exposed to the lowest CBZ and IBU concentrations, with 90 and 460-fold higher tissue concentration, respectively, after seven days. CBZ was the only substance tested which caused a significant increase in gill mRNA level of hsp70 after only one day exposure, evidencing the potential of CBZ to immediately provoke a stress condition and assumingly protein damage in gills. After longer exposure, mussels displayed down-regulated mRNA levels of hsp70 and SOD in gills, as well as of MT and P-gp in the digestive gland, hinting on an inhibitory character of CBZ. In IBU exposed mussels increased oxidant stress conditions were evidenced by induced mRNA levels in the digestive gland of CAT and MT, as well as SOD after one and four days, respectively. A concentration as found at sewage treatment plant effluents provoked an increase in transcript levels of piGST, suggesting enhanced need for biotransformation of IBU or by-products derived from oxidative stress. Also exposure to an environmentally relevant BEZ concentration provoked an immediate increase in piGST transcript level in the digestive gland followed by up-regulated hsp70 after four and seven days evidencing a chronic stress condition for the mussels.

Effect of bezafibrate on hepatic oxidative stress: comparison between conventional experimental doses and clinically-relevant doses in mice.

Several rodent studies have demonstrated that fibrate drugs can activate peroxisome proliferator-activated receptor alpha (PPARalpha) and increase reactive oxygen species (ROS) production. The persistence of strong PPARalpha activation is considered to be a possible mechanism related to the adverse effects of these agents in humans. We recently found that bezafibrate-treated mice at clinically-relevant doses (10 mg/kg/day) exhibited similar pharmacokinetics to humans, but were different from previous rodent data (> 50 mg/kg/day). To examine whether clinical doses of bezafibrate do in fact activate PPARalpha and increase hepatic oxidative stress in mice, we administered bezafibrate to wild-type and Ppara-null mice at high (100 mg/kg/day) or low (10 mg/kg/day) doses and assessed ROS-related pathways in the liver. High-dose bezafibrate increased hepatic lipid peroxides in a PPARalpha-dependent manner, likely from discordant induction of PPARalpha-regulated ROS-generating enzymes (acyl-CoA oxidase, cytochrome P450 4A, and NADPH oxidase) and enhancement of mitochondrial beta-oxidation. The treatment also activated protein kinase C and phosphatidylinositol-3-kinase in wild-type mice only, suggesting an association between strong PPARalpha activation and an altered cell signaling cascade. Meanwhile, low-dose bezafibrate reduced serum/liver triglycerides in both genotypes without activating PPARalpha or enhancing hepatic oxidative stress. These results may support the safety of bezafibrate treatment at clinically-relevant doses.

HPLC determination of bezafibrate in human plasma and its application to pharmacokinetics studies.

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.

Validation of cell-based OATP1B1 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions.

Transporters are carrier proteins that may influence pharmacokinetic, pharmacodynamic, and toxicological characteristics of drugs. The development of validated in vitro transporter models is imperative to support regulatory submissions of drug candidates. This study is focused on utilizing human embryonic kidney (HEK) 293 cell cultures genetically transfected with the human organic anion transporting polypeptides (OATP) 1B1 transporter to identify substrates and inhibitors in drug development. The kinetics of OATP1B1-mediated uptake of [(3)H]-oestradiol 17beta-glucuronide and inhibition of uptake by rifamycin SV were used to determine K(m), V(max), and IC(50) values over a range of passage numbers to investigate accuracy and precision. The mean K(m) and V(max) values were found to be 6.3 +/- 1.2 microM and 460 +/- 96 pmol min(-1) mg(-1), respectively. The mean IC(50) value for rifamycin SV was 0.23 +/- 0.07 microM on uptake of 1 microM [(3)H]-oestradiol 17beta-glucuronide. These data were similar to previously reported values (accuracy greater than 82%), reproducible (precision less than 29%) and exhibited low standard deviations (SDs) obviating the need to study test compounds on more than one occasion. [(3)H]-oestrone 3-sulfate and [(3)H]-pravastatin exhibited concentration-dependent OATP1B1 uptake, and statistically significant differences were observed at each concentration between uptake rates of HEK293-OATP1B1 and HEK293-MOCK cells (uptake ratios greater than or equal to 3). Propranolol showed no positive uptake ratio. Bezafibrate and gemfibrozil exhibited concentration-dependent inhibition of OATP1B1-mediated uptake of [(3)H]-oestradiol 17beta-glucuronide with mean IC(50) values of 16 and 27 microM, respectively. Based on the validation results, acceptance criteria to identify a test compound as a substrate and/or inhibitor using these specific cell lines were determined. These validated OATP1B1 assays were robust, reproducible, and suitable for routine in vitro evaluation of candidate drugs.

Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in mice: a novel peroxisome proliferator-activated receptor alpha-independent mechanism.

The triglyceride-lowering effect of bezafibrate in humans has been attributed to peroxisome proliferator-activated receptor (PPAR) alpha activation based on results from rodent studies. However, the bezafibrate dosages used in conventional rodent experiments are typically higher than those in clinical use (> or =50 versus < or =10 mg/kg/day), and thus it remains unclear whether such data can be translated to humans. Furthermore, because bezafibrate is a pan-PPAR activator, the actual contribution of PPARalpha to its triglyceride-lowering properties remains undetermined. To address these issues, bezafibrate at clinically relevant doses (10 mg/kg/day; low) was administered to wild-type and Ppara-null mice, and its effects were compared with those from conventionally used doses (100 mg/kg/day; high). Pharmacokinetic analyses showed that maximum plasma concentration and area under the concentration-time curve in bezafibrate-treated mice were similar to those in humans at low doses, but not at high doses. Low-dose bezafibrate decreased serum/liver triglycerides in a PPARalpha-independent manner by attenuation of hepatic lipogenesis and triglyceride secretion. It is noteworthy that instead of PPAR activation, down-regulation of sterol regulatory element-binding protein (SREBP)-1c was observed in mice undergoing low-dose treatment. High-dose bezafibrate decreased serum/liver triglycerides by enhancement of hepatic fatty acid uptake and beta-oxidation via PPARalpha activation, as expected. In conclusion, clinically relevant doses of bezafibrate exert a triglyceride-lowering effect by suppression of the SREBP-1c-regulated pathway in mice and not by PPARalpha activation. Our results may provide novel information about the pharmacological mechanism of bezafibrate action and new insights into the treatment of disorders involving SREBP-1c.

HPLC method for the determination of bezafibrate in human plasma and application to a pharmacokinetic study of bezafibrate dispersible tablet.

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%.

Improved lipid lowering activity of bezafibrate following continuous gastrointestinal administration: pharmacodynamic rationale for sustained release preparation of the drug.

PURPOSE: To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other "gastrointestinal (GI) drugs." Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. METHODS: The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. RESULTS: In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. CONCLUSIONS: The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.

Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity.

The hypocholesterolemic activity for novel ureido fibrate analogues was found to be over 100-fold greater than for any "second-generation" fibrate in cholesterol-fed rats. A comparison of 12 related analogues revealed that the optimal configuration for a urea-bridging region located between two aromatic rings consisted of a trisubstituted nitrogen, optimally substituted with a C7 alkyl chain and linked by dimethylene to a phenoxyisobutyrate moiety found in most fibrate analogues. The hypocholesterolemic potency of these compounds was found to correlate with their increased intrinsic fibrate activity as determined by the ability to induce omega-hydroxylase activity either in rat hepatocyte cultures or in vivo, and not with their 10-fold increased ACAT inhibitory potency when compared to other fibrates. The most active compound, 2-(4-(2-(N'-(2,4- difluorophenyl)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2), was found to induce omega-hydroxylase activity in hepatocytes at concentrations between 5 and 100 nM compared to 1-20 microM concentrations for bezafibrate, and lower serum VLDL+LDL cholesterol in rats at doses between 0.1 and 0.5 mg/kg per day compared to doses of 25-100 mg/kg per day for bezafibrate. Single-dose pharmacokinetic studies with 2 indicated that total drug exposure will be much lower at hypocholesterolemic doses due to the enhanced intrinsic activity, and may result in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates.

Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia.

The lipid-modifying profile of bezafibrate is characterised by marked decreases in elevated triglyceride levels, increases in high density lipoprotein (HDL) cholesterol levels and decreases in total and low density lipoprotein (LDL) cholesterol levels. Bezafibrate also reduces elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen, which are independent cardiovascular risk factors. Bezafibrate is effective in most types of primary and secondary dyslipidaemia. It is of greatest benefit in conditions featuring hypertriglyceridaemia and/or HDL cholesterol deficiency. This is particularly true for patients with diabetes mellitus, notably those with non-insulin-dependent diabetes mellitus (NIDDM) who are also likely to have increased fibrinogen levels. In the limited comparisons available, there appear to be few consistent differences in lipid-modifying effects between bezafibrate and other fibrates. Compared with HMG-CoA reductase inhibitors, bezafibrate causes larger changes in triglyceride and, in general, HDL cholesterol levels, and has a lesser influence on LDL and total cholesterol levels. These differences are advantageous when bezafibrate and HMG-CoA reductase inhibitors are used as combined therapy in patients with severe dyslipidaemia unresponsive to either modality alone. The combination of bezafibrate plus an HMG-CoA reductase inhibitor in clinical trials has not led to the predicted increase in myalgia. Indeed, bezafibrate is generally free of serious unwanted effects: rhabdomyolysis is rare and has occurred mainly in patients with renal dysfunction given excessive dosages. Other patient groups in whom bezafibrate has improved serum lipid profiles are those with isolated HDL cholesterol deficiency, dyslipidaemia secondary to renal insufficiency, and following cardiac surgery or other procedures. However, data for these indications are not extensive. Evidence is now available to show a beneficial effect of bezafibrate on retarding atherosclerotic processes and in reducing risk of coronary heart disease. The 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in young male survivors of myocardial infarction demonstrated a smaller decrease in luminal diameter and a reduction in coronary events with bezafibrate compared with placebo. The Bezafibrate Infarction Prevention (BIP) study is expected to provide mortality data which is currently lacking for bezafibrate. In conclusion, bezafibrate is a useful and well-tolerated lipid-modifying agent in the management of primary and secondary dyslipidaemia. It has particularly beneficial effects in patients with hypertriglyceridaemia and/or low HDL cholesterol levels, and reduces fibrinogen levels. Together with its ability to sustain or improve glycaemic control, these properties make it a logical choice for treating patients with diabetes mellitus and dyslipidaemia. Additionally, the drug may be of value as combination therapy in patients with severe dyslipidaemia. Importantly, there is evidence that the drug can slow the atherosclerotic process and reduce cardiovascular morbidity. The ongoing BIP secondary intervention study and other investigations will help clarify the effects of bezafibrate on cardiovascular mortality and morbidity.

Drug interactions with fibric acids.

Fibric acid derivatives may interact with other drugs and the interactions can be of clinical relevance. The pharmacological properties and effects of these drugs which pertain to their potential for drug interactions, are: (a) a very high binding affinity to plasma proteins, especially albumin; (b) the changes produced in vitamin K kinetics; (c) endoplasmic reticulum hyperplasia; (d) induction of cytochrome P450; (e) changes in xenobiotic-metabolizing enzymes; (f) their capability to have a direct effect on carbohydrate metabolism and/or regulation; and (g) potential pharmacokinetic interactions with antidiabetic drugs. Other types of interactions may affect the safety and/or the therapeutic efficacy of fibrates. These interactions are not necessarily risky, but may be important in the long term. Other clinically relevant interactions with less commonly used drugs have been described. Fibrates will continue to be used because they have proved to be safe and effective in correcting many types of dyslipidemia by reducing serum levels of total cholesterol and triglycerides and by increasing high density lipoprotein cholesterol. Furthermore, they have been proven to decrease morbidity and morality from coronary heart disease. Therefore, awareness of their potential drug interactions is most relevant to their safe clinical therapeutic use.

[Comparison of the pharmacokinetics of a quick-release bezafibrate formulation with a sustained-release formulation. 1. Single-dose administration]. / Vergleich der Pharmakokinetik einer schnellfreisetzenden Bezafibrat-Formulierung mit einer Retard-Formulierung. 1. Mitteilung: Single-dose-Applikation.

Comparison of the Pharmacokinetic Profiles of a Quick and a Sustained Release Bezafibrate Formulation/1st Communication: Single-dose application The hypolipaemic agent bezafibrate (CAS 41859-67-0) is available as immediate and sustained release formulation. The pharmacokinetic profile of an immediate release 300 mg dragee (A) was compared in a two-way cross-over design to that of a 400 mg sustained release dragee (B). Neglecting the dose difference, the AUEC of A (28.8 micrograms/ml.h) was equal to that of B (27.6 micrograms/ml.h), whereas the bioavailability of A appeared to be higher than that of B when AUEC was corrected for dose (AUEC ratio = 137%). Regarding Cmax and tmax, both formulations exhibited the expected differences.

[Comparison of the pharmacokinetics of a quick-release bezafibrate formulation with a sustained-release formulation. 2. Multiple-dose administration and chronopharmacokinetics]. / Vergleich der Pharmakokinetik einer schnellfreisetzenden Bezafibrat-Formulierung mit einer Retard-Formulierung. 2. Mitteilung: Multiple-dose-Applikation und Chronopharmakokinetik.

The pharmacokinetic profile of a 300 mg immediate release formulation (A) was compared to a 400 mg sustained release formulation (B) of the lipid lowering drug bezafibrate (CAS 41859-67-0). Preparation A was applied twice a day whereas B was applied once a day in the evening. The means of Cmax (12.5 micrograms/ml) and AUC (66.8 micrograms/ml.h) for preparation A were considerably higher than for B (Cmax: 6.6 micrograms/ml, AUC: 39.8 micrograms/ml.h), whereas no differences were found regarding Tcav (A: 8.9 h, B: 8.3 h) and PTF (A: 4.6, B; 4.1). An AUC ratio for A/B of 119% (CI90%: 108-132%) was determined after dose correction. For A an AUC/AUEC ratio of 110% was found when comparing multiple versus single-dose application, whereas this ratio with 136% appeared to be considerably higher for B. Slight chronopharmacological effects were found for preparation A, which was applied twice a day in the evening and in the morning. During night-time the AUC was (insignificantly) 12% higher than during day-time, whereas the apparent elimination halflife time was 40% longer at night (p < 0.025), which corresponded to an extended tmax of median 3 h during night-time as compared to 1.75 h at day-time.

[Long-term bezafibrate treatment in a lipid clinic].

The files of 122 patients treated for at least 6 months with bezafibrate, a second generation fibric acid derivative, were reviewed. Our indications for bezafibrate treatment included cases of type IIb, IV and V hyperlipidemia which did not respond to a serious dietetic trial. Mean decrease in plasma triglycerides was 45% and in cholesterol 1012%, while in HDL-cholesterol there was a mean increase of 8%. The drug was usually well tolerated. Thorough review of patient files for side effects revealed gastrointestinal disturbances in 6.5%. There was a decrease in libido in 4%. 2 patients developed gynecomastia, 1 abnormal liver function tests and 1 severe myositis. All side effects were fully reversed on discontinuing the drug. Bezafibrate seems to be well-tolerated and suitable for treating type IIb, IV and V hyperlipidemia unresponsive to diet.

Comparative pharmacokinetics of two oral bezafibrate preparations.

The pharmacokinetics of two oral solid preparations of bezafibrate, available in the Spanish market, was studied. Both preparations were tablets, an immediate-release formulation (A) and the other a slow-formulation (C). We selected a crossover design, and twelve healthy male volunteers participated in the study. Using a sensitive HPLC method, plasma concentrations of bezafibrate were monitored over a period of 12 h. after administration of treatment A and 24 h. for treatment C. In treatment A, two tablets were administered at an interval of six hours. The maximum plasma concentration (Cmax), time to Cmax(tmax) and area under curve (AUC infinity o), in the two doses of treatment A, were compared by analysis of variance and found to be significantly different between the two doses. The relative bioavailability based on (C: 1st-Dose-A) ratio of AUC infinity o was within the range 100 +/- 20%.