Biopharmaceutical Characterization and Bioavailability Study of a Tetrazole Analog of Clofibric Acid in Rat.

In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new clofibric acid analog (Compound 1) was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 × 10-6 cm/s in duodenum and 1.62 × 10-5 cm/s in jejunum, suggesting that Compound 1 has low permeability. Elimination constant after an oral administration of 50 µg/kg in Wistar rat was 1.81 h-1, absorption constant was 3.05 h-1, Cmax was 3.57 µg/mL at 0.33 h, AUC0-α was 956.54 µ/mL·h and distribution volume was 419.4 mL. To IV administration at the same dose, ke was 1.21 h-1, Vd was 399.6 mL and AUC0-α was 747.81 µ/mL·h. No significant differences were observed between pharmacokinetic parameters at every administration route. Bioavailability evaluated was 10.4%. Compound 1 is metabolized to Compound 2 probably by enzymatic hydrolysis, and it showed a half-life of 9.24 h. With these properties, Compound 1 would be considered as a prodrug of Compound 2 with potential as an antidiabetic and anti dyslipidemic agent.

A simple and sensitive method for the determination of fibric acids in the liver by liquid chromatography.

Fibrates are used in biochemical and pharmacological studies as bioactive tools. Nevertheless, most studies have lacked information concerning the concentrations of fibric acids working inside tissues because a simple and sensitive method is not available for their quantitation. This study aimed to develop a simple and sensitive bioanalytical method for the quantitation of clofibric, bezafibric and fenofibric acids in samples of very small portions of tissues. Fibric acids were extracted into n-hexane-ethyl acetate from tissue homogenates (10 mg of liver, kidney or muscle) or serum (100 µL) and were derivatized with 4-bromomethyl-6,7-dimethoxycoumarin, followed by HPLC with fluorescence detection. These compounds were separated isocratically on a reversed phase with acetonitrile-water. Standard analytical curves were linear over the concentration range of 0.2-20 nmol/10 mg of liver. Precision and accuracy were within acceptable limits. Recovery from liver homogenates ranged from 93.03 to 112.29%. This method enabled the quantitation of fibric acids in 10 mg of liver from rats treated with clofibric acid, bezafibric acid or fenofibrate. From these analytical data, it became clear that there was no large difference in ratio of acyl-CoA oxidase 1 (Acox1) mRNA level to fibric acid content in the liver among the three fibric acids, suggesting that these three fibric acids have similar potency to increase expression of the Acox1 gene, which is a target of peroxisome proliferator-activated receptor α. Thus, the proposed method is a simple, sensitive and reliable tool for the quantitation of fibric acids working in vivo inside livers.

Efecto de la expresión de la PTEC, el gemfibrozilo y la rosiglitazona en el transporte inverso de colesterol desde macrófagos a heces in vivo / The effect of human CETP activity, gemfibroziland rosiglitazone on macrophage-specific reverse cholesterol transport in vivo

Introducción. La expresión de PTEC humana enratones transgénicos reduce el colesterol de las lipoproteínas de alta densidad (cHDL) y aumenta la susceptibilidad a la arteriosclerosis. Por otro lado, el gemfibrozilo, uno de los fibratos más utilizados en clínica, y la rosiglitazona aumentan el cHDL y reducen la susceptibilidad a la arteriosclerosis en modelos murinos. El objetivo principal de este estudio es evaluar el efecto de la expresión de la PTEC humana, el gemfibrozilo y la rosiglitazona en el transporte inverso de colesterol(TIC) específico de macrófagos. Materiales y método. Para determinar el TIC específico de macrófagos se aplicó inyección intraperitoneal de macrófagos P388D1 marcados con 3H-colesterol en ratones controles (C57BL/6) y ratones transgénicos de PTEC humana. Este mismo proceso se realizó en ratones transgénicos de apoA-I humana (h) que recibieron una dosis diaria por vía oral de gemfibrozilo (625 mg/kg) orosiglitazona (10 mg/kg) durante 17 días y se los comparó con los que recibieron la solución vehículo. A las 48 h, se sacrificó a los animales y se determinó el 3H-colesterol en plasma, hígado y heces. Resultados. Los ratones transgénicos de PTEC humana presentaron una disminución significativa de cHDL en plasma respecto a los ratones controles. El gemfibrozilo incrementó el colesterol total y el cHDL en los ratones transgénicos deapoA-Ih. Sin embargo, ni la expresión de PTEC humana ni los tratamientos farmacológicos alteraron la excreción fecal de colesterol y ácidos biliares. No se encontraron diferencias significativas en el TIC de 3H-colesterol desde los macrófagos P388D1 a heces en los diferentes grupos experimentales. Conclusiones. Ni la expresión de PTEC humana en ratones transgénicos ni el tratamiento congemfibrozilo o rosiglitazona en ratones transgénicos de apoA-Ih modifican el transporte inverso de colesterol especifico de macrófagos in vivo (AU)

Background. Human CETP expression in micereduces cholesterol from high density lipoprotein HDLc) and increases atherosclerosis susceptibility. On the other hand, gemfibrozil, one of the most used fibrates in clinical practice, and rosiglitazone, increase HDLc and reduce the atherosclerotic susceptibility in mouse models of atherosclerosis. The main aim of this study was to evaluate the effect of human CETP expression, and the effect of gemfibrozil or rosiglitazone treatment on one of the most important HDL anti-atherogenic properties, the macrophage-specific reverse cholesterol transport (RCT).Materials and method. To determinate the macrophage-specific RCT, [3H]cholesterol-labelledP388D1 macrophages were injected intraperitoneally into control mice (C57BL/6) and into human CETP transgenic mice. We performed the same procedure in human apoA-I transgenic mice treated during 17 days with an oral daily gavage dose of gemfibrozil (625 mg/kg),rosiglitazone (10 mg/kg) or vehicle solution. At 48h, the mice were euthanized and [3H]cholesterol in plasma, liver and faeces were measured. Results. Human CETP transgenic mice showed decreased HDLc compared to control mice. Human apoA-I transgenic mice showed an increase in total cholesterol and HDLc when treated with gemfibrozil, but not with rosiglitazone. Neither the human CETP activity, nor either of the two pharmacological treatments altered faecal cholesterol or bile acid excretion. Furthermore, the[3H]tracer detected in liver, faecal cholesterol and bile acid was not significantly different in any of the animal groups. Conclusions. Neither human CETP expression intransgenic mice, nor treatment with gemfibrozil orrosiglitazone in human apoA-I transgenic micemodified macrophage-specific reverse cholesterol transport (AU)

Toxicity and removal efficiency of pharmaceutical metabolite clofibric acid by Typha spp.--potential use for phytoremediation?

A study was conducted to assess Typha spp.'s ability to withstand and remove, from water, a metabolite of blood lipid regulator drugs, clofibric acid (CA). At a concentration of 20 microg L(-1), Typha had removed >50% of CA within the first 48h, reaching a maximum of 80% by the end of the assay. Experimental conditions assured that photodegradation, adsorption to vessel walls and microbial degradation did not contribute to the removal. Exposure to higher CA concentrations did not affect Typha's photosynthetic pigments but the overall increase in enzyme activity (ascorbate and guaiacol peroxidases, catalase, superoxide dismutase) indicates that both roots and leaves were affected by the xenobiotic. Eventually, Typha seemed able to cope with the CA's induced oxidative damage suggesting its ability for phytoremediation of CA contaminated waters.

Modulación del PPARalfa por agentes farmacológicos y naturales y sus implicaciones metabólicas / PPARalpha modulation by pharmacological and natural agents and metabolic implications

El receptor activado por proliferadores peroxisómicos tipo alfa (PPAR alfa) une ácidos grasos, eicosanoides o fibratos, y regula la transcripción de genes relacionados tanto con el metabolismo lipídico y glucídico como con la inflamación. Los fibratos son ligandos de PPAR alfa que se utilizan para normalizar diversos parámetros lipídicos y glucídicos y que ejercen efectos antiinflamatorios. De hecho, se ha demostrado que los fibratos producen mejoras en los pacientes con síndrome metabólico, diabetes mellitus de tipo 2 y enfermedades cardiovasculares. Este artículo revisa el mecanismo de acción y los papeles funcionales de los fibratos, enfatizando los factores que modulan su capacidad para activar PPAR alfa y que por tanto pueden afectar su efectividad. Estos factores podrían explicar los resultados obtenidos en experimentos con animales y en estudios clínicos con fibratos en los que se encontraron efectos adversos y/o una ineficiente acción hipolipemiante tras la activación del PPAR alfa. Por lot anto, todos esos resultados han subrayado la necesidad de buscar otros fármacos o agentes nutricionales que modulen el PPAR alfa. Esta estrategia podría ser complementaria o bien reemplazar al tratamiento clásico. Así, revisamos brevemente los nuevos ligandos naturales y sintéticos del PPAR alfa que se están desarrollando actualmente y que son más específicos, selectivos, con más potencia y que, en principio, presentan mayor efectividad y menos efectos adversos que los fibratos (AU)

Peroxisome proliferator-activated receptor alpha (PPAR alpha) binds fatty acids, eicosanoids, or fibrates, and regulates transcription of genes involved both in lipid and glucose metabolism as well as in inflammation. Fibrates are PPAR alpha ligands used to normalize lipid and glucose parameters and exertanti-inflammatory effects. In fact, fibrates have already been demonstrated to benefit metabolic syndrome, type 2 diabetes and cardiovascular diseases. This article reviews the mechanism of action and the functional roles of fibrates, emphasising the factors modulating their capacity to activate PPAR apha and affecting their effectiveness. These factors would possibly explain the findings obtained in animal studies and clinical trials with fibrates which showed either untoward effects and/or inefficient hypolipidemic action of PPAR alphaactivation. Therefore, all those findings have underlined the need to search for pharmacological or nutritional solutions based on modulation of PPAR alpha. This strategy could either be complementary to or replace the classical therapy. Thus, a brief survey of the natural and synthetic agonists of PPAR alpha, more specific, selective, with higher potency and, supposedly, displaying greater effectiveness and fewer adverse effects than fibrates which are currently being developed, isa lso mentioned (AU)

Differential effects of fibrates on the metabolic activation of 2-phenylpropionic acid in rats.

A series of studies were conducted to explore the inductive potential of different fibric acid derivatives on the two alternative metabolic activation pathways of 2-phenylpropionic acid (2-PPA) (a model substrate for profen drugs), namely acyl-CoA formation and acyl glucuronidation, in vivo in rats, and to evaluate whether such treatment could potentially modulate the covalent binding of profens to hepatic protein. After administration of a single dose of 2-PPA (130 mg/kg) to rats pretreated with equimolar doses of clofibric acid (160 mg/kg/day), fenofibrate (260 mg/kg/day), or gemfibrozil (180 mg/kg/day) for 7 days, rat livers were collected and analyzed for covalent binding and hepatic levels of the two reactive metabolites over a 2-h period. Results showed that the three fibrates exhibited very different effects on the hepatic levels of 2-PPA-S-acyl CoA (2-PPA-CoA) in vivo, even though all three significantly increased acyl-CoA synthetase activity in vitro in liver homogenate. Treatment with clofibric acid markedly increased the hepatic exposure of 2-PPA-CoA by 2.9-fold and led to a 25% increase (p < 0.05) in covalent binding of 2-PPA to liver protein. In contrast, significant decreases of the hepatic levels of 2-PPA acyl glucuronide and/or 2-PPA-CoA by fenofibrate and gemfibrozil significantly lowered the covalent binding of 2-PPA to hepatic protein. Together, these results suggest that fibrates exhibit markedly different abilities to alter the extent of covalent binding of 2-PPA to hepatic protein by differentially modulating the hepatic exposure of the two reactive metabolites of 2-PPA, namely 2-PPA-CoA thioester and acyl glucuronide.

Stearoyl-CoA desaturase activity is elevated by the suppression of its degradation by clofibric acid in the liver of rats.

A mechanism by which fibrates control stearoyl-CoA desaturase (SCD) in the liver was studied. Treatment of rats with 2-(4-chlorophenoxy)-2-methylpropionic acid (clofibric acid) or feeding of a fat-free diet markedly elevated hepatic activity of SCD. Both the treatment with clofibric acid and the feeding of the fat-free diet caused an increase in the steady-state level of SCD1 mRNA and enhanced transcriptional rate. The half-lives of SCD for control rats, rats treated with clofibric acid rats, and rats fed the fat-free diet were estimated to be 2.0, 3.9, and 1.9 h, respectively. Activity of palmitoyl-CoA chain elongase (PCE) was increased by both clofibric acid treatment and feeding of the fat-free diet as was observed with SCD. Steady-state level of rat fatty acid elongase 2 mRNA was increased by the treatment with clofibric acid or feeding of fat-free diet, although the transcriptional rate was not altered. Different from SCD, PCE was highly stable and its half-life was not changed by either clofibric acid or fat-free diet. These results strongly suggest that the decreased degradation of SCD is responsible for the increase in its activity in addition to increased transcription of SCD1 in the rats treated with clofibric acid.

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions.

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug-drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.

Pharmacokinetic interactions between statins and fibrates.

Concomitant use of a fibrate and a statin may offer a therapeutic advantage to patients with dyslipidemia, especially in patients whose low-density lipoprotein cholesterol is controlled by statins but whose high-density lipoprotein cholesterol or triglycerides, or both, are not within goal. However, concern about drug-drug interactions may preclude optimal use of combination statin-fibrate therapy. This article reviews the pharmacokinetics between statins and fibrates, addressing risks associated with drug-drug interactions and combination therapy.

Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver.

Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARalpha agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood. Cynomolgus monkeys were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Strong upregulation of many genes relating to fatty acid metabolism and mitochondrial oxidative phosphorylation was observed; this reflects the known pharmacology and activity of the fibrates. In addition, (1) many genes related to ribosome and proteasome biosynthesis were upregulated, (2) a large number of genes downregulated were in the complement and coagulation cascades, (3) a number of key regulatory genes, including members of the JUN, MYC, and NFkappaB families were downregulated, which appears to be in contrast to the rodent, where JUN and MYC are reported to upregulated after PPARalpha agonist treatment, (4) no transcriptional signal for DNA damage or oxidative stress was observed, and (5) transcriptional signals consistent with an anti-proliferative and a pro-apoptotic effect were seen. We also compared the primate data to literature reports of hepatic transcriptional profiling in PPARalpha-treated rodents, which showed that the magnitude of induction in beta-oxidation pathways was substantially greater in the rodent than the primate.

[Conjugation reactions of ciprofibrate with human and laboratory animals]. / Konjugationsreaktionen von Ciprofibrat bei Menschen und Versuchstieren.

An open problem of the lipid lowering agent ciprofibrate (rac-2-[4-(2,2-dichlorocyclopropyl)-phenoxy]-2-methylpropanoic acid, CAS 52214-84-3) is its metabolism concerning the conjugation with amino acids and glucuronic acid. It could be solved by syntheses of the needed reference compounds--unknown up to now--and administration of ciprofibrate to volunteers and rats. Unexpectedly the conjugation compounds with amino acids are stable in vitro and in metabolism. There was no evidence for any conjugation reaction with amino acids by investigating samples of urine and faeces. On the contrary the urine of humans contains 90-97% of beta-O-acylglucuronide, whereas rat urine shows only 10% of the calculated amount.

Interaction of gamma-glutamyltranspeptidase with clofibryl-S-acyl-glutathione in vitro and in vivo in rat.

Clofibric acid (CA) is metabolized to chemically reactive acylating products that can transacylate glutathione to form clofibryl-S-acyl-glutathione (CA-SG) in vitro and in vivo. We investigated the first step in the degradation of CA-SG to the mercapturic acid conjugate, clofibryl-S-acyl-N-acetylcysteine (CA-SNAC), which is catalyzed by gamma-glutamyltranspeptidase (gamma-GT). After gamma-GT mediated cleavage of glutamate from CA-SG, the product clofibryl-S-acyl-cysteinylglycine (CA-S-CG) should undergo an intramolecular rearrangement reaction [Tate, S. S. (1975) FEBS Lett. 54, 319-322] to form clofibryl-N-acyl-cysteinylglycine (CA-N-CG). We performed in vitro studies incubating CA-SG with gamma-GT to determine the products formed, and in vivo studies examining the products excreted in urine after dosing rats with CA-SG or CA. Thus, CA-SG (0.1 mM) was incubated with gamma-GT (0.1 unit/mL) in buffer (pH 7.4, 25 degrees C) and analyzed for products formed by reversed-phase HPLC and electrospray mass spectrometry (ESI/MS). Results showed that CA-SG is degraded completely after 6 h of incubation leading to the formation of two products, CA-N-CG and its disulfide, with no detection of CA-S-CG thioester. After 36 h of incubation, only the disulfide remained in the incubation. Treatment of the disulfide with dithiothreitol led to the reappearance of CA-N-CG. ESI/LC/MS analysis of urine (16 h) extracts of CA-SG-dosed rats (200 mg/kg, iv) showed that CA-SG is degraded to CA-N-CG, CA-N-acyl-cysteine (CA-N-C) and their respective S-methylated products. The mercapturic acid conjugate (CA-SNAC) was found as a minor product. Analysis of urine extracts from CA-dosed rats (200 mg/kg, ip) resulted in the detection of clofibryl-N-acyl-cysteine (CA-N-C), but no evidence for the formation of CA-SNAC was obtained. These in vitro and in vivo experiments indicate that gamma-GT mediated degradation of clofibryl-S-acyl-glutathione leads primarily to the formation and excretion of clofibryl-N-acyl-cysteine products rather than the S-acyl-NAC conjugate.

Cleavage of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates.

The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates is reported. Amidomethyl esters are rapidly and quantitatively converted to the corresponding acid and secondary amide. Reactivity is inversely dependent upon the molar refractivity and lipophilicity of the ester, as well as with steric bulk in the carboxylic acid moiety. In contrast to chemical and plasma hydrolyses, no dependence upon the pK(a) of the carboxylate leaving group was observed, nor was there any dependence upon the amide N-substituent. The rate of decomposition was inhibited by the carboxylesterase inhibitor eserine but not by the cytochrome P450 inhibitor SKF-525A, indicating the involvement of esterases in the hydrolysis reaction. These results indicate that amidomethyl esters may be expected to be readily cleaved in vivo.

Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days.

The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were investigated after 23 days of ciprofibrate (100 mg or 200 mg) therapy or fenofibrate (200 mg) therapy. In a double-blind, double-placebo, cross-over study, three groups of six healthy volunteers received either 100 mg ciprofibrate/day followed by 200 mg fenofibrate 'high bioavailability' (HB)/day, or vice versa (group A), 200 mg ciprofibrate HB/day followed by 200 mg fenofibrate HB/day, or vice versa (group B), or 100 mg ciprofibrate/day followed by 200 mg ciprofibrate/day, or vice versa (group C). Fasting plasma lipid levels and safety parameters were evaluated before and after treatment. One hundred milligrams ciprofibrate/day therapy was found to be approximately as effective as 200 mg fenofibrate HB/day therapy in altering the lipid profile. The highest activation of LPL was obtained after treatment with 200 mg ciprofibrate/day. A modest, but statistically significant, increase in HL activity was found after 100 or 200 mg ciprofibrate treatment. Investigation of the pharmacokinetics of ciprofibrate and fenofibric acid revealed a shorter time to reach peak plasma levels, but a longer elimination half life for the ciprofibrate preparations in comparison with fenofibrate. A dose of 200 mg ciprofibrate/day is more effective than 100 mg ciprofibrate/day at increasing LPL and HL activity; however, 200 mg ciprofibrate/day is also associated with a potential detrimental change in safety parameters. Two hundred milligrams fenofibrate HB/day therapy may represent an alternative therapy to 100 mg ciprofibrate/day for hyperlipidaemic patients.

Difference between guinea pig and rat in the liver peroxisomal response to equivalent plasmatic level of ciprofibrate.

Guinea pig was previously classified as a species nonresponsive to peroxisome proliferators. However, none of the previous reports was based on pharmacokinetic data. Here, after a comparative pharmacokinetic study between the guinea pig and rat, we evaluate the guinea pig liver peroxisomal response to ciprofibrate, a hypolipemic agent and a potent peroxisome proliferator in rat. (1) Pharmacokinetic results show equivalent in guinea pig and rat when guinea pigs are treated with ciprofibrate at 30 mg/kg twice a day and rats are treated at 3 mg/kg once a day. (2) The treatment of guinea pigs at 30 mg/kg twice a day for 2 weeks leads to a significant increase in the liver peroxisomal palmitoyl-CoA oxidase activity (x 1.6) and also in the microsomal omega-laurate hydroxylase activity (x 1.8). These increases are in accordance with the changes in polypeptide patterns of isolated liver peroxisomes as well as in the immunoblotting of acyl-CoA oxidase. It is deduced that a weak, but significant, peroxisome proliferation can occur in guinea pig liver after a ciprofibrate treatment at dosages corresponding to equivalent plasmic concentrations of the drug between guinea pig and rat. (3) The hybridization of guinea pig liver RNA with the rat liver-inducible acyl-CoA oxidase cDNA probe shows a decrease in the corresponding heterologous mRNA content after treatment with ciprofibrate at 30 mg/kg twice a day. This result contrasts with the slight increase observed in immunodetection and in enzymatic assays, suggesting the existence of at least two different acyl-CoA oxidases in guinea pig liver peroxisomes.

[Pharmacokinetics of clofibrate in jaundiced newborn infants at term]. / Pharmacocinétique du clofibrate chez le nouveau-né à terme ictérique.

BACKGROUND: Clofibrate (CFB) has been proposed to increase elimination of bilirubin in neonates with hyperbilirubinemia. Nevertheless, its disposition, at this age, remains unknown. The aim of this work was to characterize pharmacokinetics of an oil formulation of CFB in neonates at term with jaundice. PATIENTS AND METHODS: Two groups (G1 and G2) of eight neonates, presenting with jaundice, entered an open, non randomized and comparative study. Five blood samples were collected over 50 hours following a single oral administration of 100 mg/kg or 50 mg/kg CFB, respectively, in G1 and G2. Serum concentrations of both CFB and clofibric acid (CFA) were measured by HPLC and the pharmacokinetic analysis was made by a non-compartmental method. Data were compared to those obtained in adults receiving 2 g dose of CFB. RESULTS: Tolerance to the treatment was excellent. Pharmacokinetic profiles were similar in both groups of infants. There was a slow and prolonged formation of CFA whose serum concentrations remained high 50 hours after drug administration. Non-hydrolyzed CFB was found in the blood of three neonates. Elimination of CFA was prolonged corresponding to a terminal half-life (t1/2m) often above 100 hours and sometimes incalculable. MRTo-->50 (h) was similar in both groups (ie 26.2 +/- 2.0 vs 25.5 +/- 1.3, respectively). The decrease of t1/2m was related to the decrease of the clearance of CFA. CONCLUSIONS: The decrease in CFB's metabolism in newborns is probably the result of at least two concurrent phenomenons: partial hydrolysis of CFA, especially at high doses, and decrease in the hepatic capacity to conjugate the active metabolite. A single oral administration of 50 mg/kg CFB seems to be a suitable schedule.

Characterization and formation of the glutathione conjugate of clofibric acid.

The incubation of 1-O-clofibryl glucuronide (1-O-CAG), a metabolite of clofibrate, with glutathione (GSH) resulted in the appearance of a new peak when analyzed by HPLC. The use of HPLC coupled to electrospray-MS permitted the identification of the peak as S-(p-chlorophenoxy-2-methylpropanoyl)glutathione (CA-SG), formed by nucleophilic displacement of the glucuronide moiety from 1-O-CAG. Conjugate formation was enhanced 8-fold by rat liver glutathione S-transferases (GSTs). GSH was unreactive with isomers of 1-O-CAG formed by acyl migration, indicating that 1-O-CAG itself was the preferred substrate. Rearrangement of 1-O-CAG to its isomers in vitro, was found to be decreased in the presence of GSH. In vivo studies indicated that, following an intravenous infusion of clofibric acid to rats (75 mg/kg), the concentration of CA-SG excreted in bile over 4 hr, was approximately 0.1% of the concurrent CAG concentrations. Although these results indicate a minor role for GST-catalyzed reactions in clofibrate metabolism in vivo, they do define 1-O-acyl-linked glucuronides as a new class of substrates for GSTs.

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.

[The pharmacokinetics of hypolipemic agents. 10. The dehalogenation of the hypolipemic agent ciprofibrate]. / Zur Pharmakokinetik von Lipidsenkern, 10. Mitt.: Zweiter Beitrag zur Frage der Dehalogenierung des Lipidsenkers Ciprofibrat.

rac-2 described as a metabolite of rac-1 was synthesized in four steps starting with rac-3. Partial dehalogenation occurs with LiAlH4. A new structure assignment of the resulting stereoisomers resulted from NMR spectroscopy. After oral administration of rac-1 in multiple dose studies to volunteers, rac-2 could not be detected within the limitations of sensitivity of HPLC (UV-detector) in plasma or in urine.

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.