Assessment of Preclinical Liver and Skeletal Muscle Biomarkers Following Clofibrate Administration in Wistar Rats.

Clofibrate is a known rodent hepatotoxicant classically associated with hepatocellular hypertrophy and increased serum activities of cellular alanine aminotransferase/aspartate aminotransferase (ALT/AST) in the absence of microscopic hepatocellular degeneration. At toxic dose, clofibrate induces liver and skeletal muscle injury. The objective of this study was to assess novel liver and skeletal muscle biomarkers following clofibrate administration in Wistar rats at different dose levels for 7 days. In addition to classical biomarkers, liver injury was assessed by cytokeratin 18 (CK18) cleaved form, high-mobility group box 1, arginase 1 (ARG1), microRNA 122 (miR-122), and glutamate dehydrogenase. Skeletal muscle injury was evaluated with fatty acid binding protein 3 (Fabp3) and myosin light chain 3 (Myl3). Clofibrate-induced hepatocellular hypertrophy and skeletal muscle degeneration (type I rich muscles) were noted microscopically. CK, Fabp3, and Myl3 elevations correlated to myofiber degeneration. Fabp3 and Myl3 outperformed CK for detection of myofiber degeneration of minimal severity. miR-122 and ARG1 results were significantly correlated and indicated the absence of liver toxicity at low doses of clofibrate, despite increased ALT/AST activities. Moreover, combining classical and novel biomarkers (Fabp3, Myl3, ARG1, and miR-122) can be considered a valuable strategy for differentiating increased transaminases due to liver toxicity from skeletal muscle toxicity.

Different induction of LPA receptors by chemical liver carcinogens regulates cellular functions of liver epithelial WB-F344 cells.

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6 ) mediates a variety of cellular functions, including cell motility. In the present study, we investigated the effects of LPA receptors on cell motile activity during multi-stage hepatocarcinogenesis in rat liver epithelial WB-F344 cells treated with chemical liver carcinogens. Cells were treated with a initiator (N-nitrosodiethylamine (DEN)) and three promoters (phenobarbital (PB), okadaic acid (OA) and clofibrate) every 24 h for 2 days. Cell motile activity was elevated by DEN, correlating with Lpar3 expression. PB, OA, and clofibrate elevated Lpar1 expression and inhibited cell motile activity. To evaluate the effects of long-term treatment on cell motility, cells were treated with DEN and/or PB for at least 6 months. Lpar3 expression and cell motile activity were significantly elevated by the long-term DEN treatment with or without further PB treatment. In contrast, long-term PB treatment with or without further DEN elevated Lpar1 expression and inhibited cell motility. When the synthesis of extracellular LPA was blocked by a potent ATX inhibitor S32826 before cell motility assay, the cell motility induced by DEN and PB was markedly suppressed. These results suggest that activation of the different LPA receptors may regulate the biological functions of cells treated with chemical carcinogens. © 2015 Wiley Periodicals, Inc.

Treatment with pharmacological PPARα agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents.

BACKGROUND: Treatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor α (PPARα), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPARα leads to an up-regulation of the ubiquitin proteasome system (UPS) which plays a major role in protein degradation in muscle. METHODS: Rats, wild-type and PPARα-deficient mice (PPARα(-/-)) were treated with synthetic PPARα agonists (clofibrate, WY-14,643) to study their effect on the UPS and myofibrillar protein breakdown in muscle. RESULTS: In rats and wild-type mice but not PPARα(-/-) mice, clofibrate or WY-14,643 caused increases in mRNA and protein levels of the ubiquitin ligases atrogin-1 and MuRF1 in muscle. Wild-type mice treated with WY-14,643 had a greater 3-methylhistidine release from incubated muscle and lesser muscle weights. In addition, wild-type mice but not PPARα(-/-) mice treated with WY-14,643 had higher amounts of ubiquitin-protein conjugates, a decreased activity of PI3K/Akt1 signalling, and an increased activity of FoxO1 transcription factor in muscle. Reporter gene and gel shift experiments revealed that the atrogin-1 and MuRF1 promoter do not contain functional PPARα DNA-binding sites. CONCLUSIONS: These findings indicate that fibrates stimulate ubiquitination of proteins in skeletal muscle which in turn stimulates protein degradation. Up-regulation of ubiquitin ligases is probably not mediated by PPARα-dependent gene transcription but by PPARα-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1. GENERAL SIGNIFICANCE: PPARα plays a role in the regulation of the ubiquitin proteasome system.

Topical clofibrate improves symptoms in patients with atopic dermatitis and reduces serum TARC levels: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Though topical corticosteroids (TC) are used for treating atopic dermatitis (AD) as a standard, there exist several problems including topical steroid addiction (TSA) or Red skin syndrome. Moreover, the number of patients, who refrain from using TC because of steroid-phobia, is increasing. Recently, topical PPAR alpha ligand application has been reported to improve experimental allergic dermatitis. The purpose of this study was to investigate the short-term efficacy and safety of topical clofibrate, one of PPAR alpha ligand, in such steroid-phobic patients with AD. METHODS: This study was conducted as a double-blind design to investigate the effects of random administration of topical clofibrate and base (placebo) on skin manifestation and blood parameters of patients for 2 weeks. Severity was digitized using severity scoring systems for atopic dermatitis by the Japanese Dermatological Association (SSS-JDA) before and after two weeks. Subjective severity of patients was evaluated using visual analog scale (Pt-VAS). Serum thymus and activation-regulated chemokine (TARC) and immunoglobulin E (IgE) were also investigated. RESULTS: Twenty patients were enrolled, and 19 of 20 patients completed the study. In 19 patients, the value of severity score using SSS-JDA was decreased significantly after administration of topical clofibrate (P=0.001). Subjective evaluation using Pt-VAS (P=0.008) and serum TARC levels (P=0.03) were also significantly decreased after two weeks of topical clofibrate. There was not a significant difference in serum IgE levels. No adverse effect was observed. CONCLUSIONS: Topical clofibrate is useful for patients with AD especially who are reluctant to use topical steroids.

Peroxisome proliferator-activated receptor α agonist-induced histidine decarboxylase gene expression in the rat and mouse liver.

By analysis of the data from the Toxicogenomics Database (TG-GATEs), histidine decarboxylase gene (Hdc) was identified as largely and commonly upregulated by three fibrates, clofibrate, fenofibrate, and WY-14,643, which are known to induce hepatocellular hypertrophy and proliferation via stimulation of peroxisome proliferator-activated receptor α (PPARα) in rodents. As histamine has been reported to be involved in the proliferation of liver cells, the present study was conducted to focus on Hdc. Among other genes related to histidine and histamine, the expression of the gene of histamine ammonia lyase (Hal) was exclusively mobilized by the three fibrates. The expression of Hdc, which was usually very low in the liver, was increased with the repeated administration of fibrates, and concomitantly, the constitutive expression of Hal was suppressed. An interpretation is that the formation of urocanic acid from histidine under the normal condition switches to the formation of histamine. The mobilization of gene expression of Hdc and Hal by PPARα agonists could not be reproduced in primary cultured hepatocytes. The Hdc mRNA appeared to be translated to a protein which is processed differently from brain but similarly to gastric mucosa. Surprisingly, the fibrates caused hepatic hypertrophy but no induction of Hdc mRNA at all in mice. These results revealed that the changes in the histidine catabolism by PPARα agonists might be partially, but not directly, involved in the hepatocyte proliferation in rats, and there is a large genetic distance even between rat and mouse.

Sex-steroids and hypolipidemic chemicals impacts on brown trout lipid and peroxisome signaling - Molecular, biochemical and morphological insights.

Lipid metabolism involves complex pathways, which are regulated in a similar way across vertebrates. Hormonal and hypolipidemic deregulations cause lipid imbalance from fish to humans, but the underlying mechanisms are far from understood. This study explores the potential of using juvenile brown trout to evaluate the in vivo interferences caused by estrogenic (17α-ethinylestradiol - EE2), androgenic (testosterone - T), and hypolipidemic (clofibrate - CLF) compounds in lipidic and/or peroxisomal pathways. Studied endpoints were from blood/plasma biochemistry, plasma fatty acid profile, ultrastructure of hepatocytes and abundance of their peroxisomes to mRNA expression in the liver. Both T and CLF caused minimal effects when compared to EE2. Estrogenized fish had significantly higher hepatosomatic indexes, increased triglycerides and very-low density lipoproteins (VLDL) in plasma, compared with solvent control. Morphologically, EE2 fish showed increased lipid droplets in hepatocytes, and EE2 and T reduced volume density of peroxisomes in relation to the hepatic parenchyma. Polyunsaturated fatty acids (PUFA) in plasma, namely n-3 PUFA, increased with EE2. EE2 animals had increased mRNA levels of vitellogenin A (VtgA), estrogen receptor alpha (ERα), peroxisome proliferator-activated receptor alpha (PPARα), PPARαBa and acyl-CoA long chain synthetase 1 (Acsl1), while ERß-1, acyl-CoA oxidase 1-3I (Acox1-3I), Acox3, PPARγ, catalase (Cat), urate oxidase (Uox), fatty acid binding protein 1 (Fabp1) and apolipoprotein AI (ApoAI) were down-regulated. In summary, in vivo EE2 exposure altered lipid metabolism and peroxisome dynamics in brown trout, namely by changing the mRNA levels of several genes. Our model can be used to study possible organism-level impacts, viz. in gonadogenesis.

Clofibrate treatment in pigs: effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents.

BACKGROUND: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species. RESULTS: Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05). CONCLUSION: The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis.

Gemfibrozil-induced myopathy.

Drug-induced myopathy has been reported with use of lovastatin, nicotinic acid, and clofibrate. A particularly severe form, often accompanied by rhabdomyolysis, has been reported with the use of lovastatin and gemfibrozil; however, as far as we know, no case has been documented with use of gemfibrozil alone. Herein, we report the first case (to our knowledge of gemfibrozil-induced myopathy, confirmed by drug rechallenge.

Comparative efficacy of colestipol and clofibrate in type IIa hyperlipoproteinemia.

A multiclinic study was performed comparing colestipol hydrochloride, clofibrate, and placebo in 245 patients with type IIa hyperlipoproteinemia. Eighty-five subjects took colestipol hydrochloride in progressive doses of 15, 20, and 30 g/day; 87 took 2.0 g/day of clofibrate; and 73 took placebo over the six months of study. Colestipol lowered total cholesterol level 20.9% in comparison with clofibrate (14.6%) (statistically significant at months 3, 5, and 6), and lowered low-density lipoprotein cholesterol level 28.8% in comparison with clofibrate (14.8%) (significant at months 2, 4, and 6, all times measured). High-density lipoprotein cholesterol level remained unchanged in all groups. Clofibrate lowered total triglyceride levels 22.5%, compared with an increase of 12.5% in the colestipol group and 11.1% in the placebo group (significant at all time intervals). Colestipol was more effective than clofibrate in lowering the cholesterol fractions associated with increased cardiovascular risk.

[Mechanisms of hepatotoxicity]. / Mecanismos de hepatotoxicidade.

Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes) without cholestatic alterations (bilirubin and or alkaline phosphatase increases). Six mechanisms were proposed for hepatotoxicity: 1. High energy reactions on P450 cytochrome impairing calcium homeostasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity). 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated). 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of hypolipidemic drugs, interaction with other drugs, and previous active liver disease might increase liver toxicity.

[Hypolipidemic therapy in special situations: hypothyroidism and liver disease]. / Terapia hipolipemiante em situações especiais--hipotireoidismo e hepatopatias.

Hypothyroidism is common in the elderly, especially among women. It should be suspected in the presence of classic signals and symptoms, and can be detected by an elevation of serum thyroid stimulating hormone (TSH). Lipid abnormalities in the presence of subclinical hypothyroidism are of minor importance. However, the importance of specific treatment (hormone replacement) increases with the magnitude of thyroid disturbance. Some hypolipidemic agents can aggravate prior liver disease, however, recent studies have shown that statins might be useful in the presence of steatohepatitis. Some associations of hypolipidemic drugs can increase liver enzymes, and careful monitoring is recommended.

Control of clofibrate toxicity in uremic hypertriglyceridemia.

A daily dose of 1.5 to 2.0 gm of clofibrate lowers serum triglyceride (TG) levels in patients with normal renal function but causes muscle toxicity and elevated creatine phosphokinase (CPK) levels in patients with long-term renal failure. Plasma clofibrate disappearance is prolonged as much as seven times normal in severely uremic patients. A marked reduction in the standard 14 gm/wk clofibrate dose to a total dose of 1.0 to 1.5 gm/wk effectively lowered serum TG levels (--28%, p less than 0.02) in hypertriglyceridemic hemodialysis patients without toxicity. The serum clofibrate level at this dose was comparable to that in hypertriglyceridemic nonuremic patients receiving 14 gm/wk of clofibrate. The dose of clofibrate administered to hemodialysis patients can be adjusted to avoid toxicity and provide the desired therapeutic effect by monitoring serum CPK and TG levels.

Long-term treatment of type III hyperlipoproteinemia with clofibrate.

In this retrospective study we report the results of treatment with clofibrate during at least 7 years in 9 patients with severe type III hyperlipoproteinemia. Initial treatment consisted of a diet, restricted in fat and calories, because of insufficient response additional therapy with 2 g clofibrate daily was given. Serum cholesterol decreased significantly from 14.3 +/- 4.4 mmol/l (mean +/- SD), on diet therapy, to average annual values ranging from 9.0 +/- 4.9 to 7.9 +/- 2.0 and serum triglycerides decreased significantly from 5.6 +/- 1.9 to average annual values from 3.8 +/- 1.8 to 2.0 +/- 0.7, despite a slight gain in bodyweight. Serious side-effects did not occur. After several years of treatment with clofibrate the drug was withdrawn temporarily. Serum lipids increased significantly in all patients to a level, not different from that before the start of drug therapy. It is concluded that clofibrate is a strong hypolipidemic drug for the treatment of type III hyperlipoproteinemia, which does not lose efficacy even after 7 years of use.

Effects of ciprofibrate on LDL metabolism in man.

This study examined the effects of ciprofibrate therapy (100 mg/day) on plasma lipids, lipoproteins and low density lipoprotein (LDL) kinetic heterogeneity in moderately hypercholesterolaemic subjects. The drug lowered plasma triglyceride and cholesterol by 41% and 17%, respectively. Very low density lipoprotein (VLDL) cholesterol fell by 38%, LDL cholesterol fell by 22%, while the content of the lipid in high density lipoprotein (HDL) increased by 11%. LDL structural and metabolic heterogeneity were assessed before and during therapy in eight subjects. Density gradient centrifugation was used to fractionate LDL into three species. LDL-I, the least dense, was not affected by therapy whereas LDL-II and LDL-III were decreased by 28% (P < 0.01) and 31% (N.S.). Baseline turnover studies revealed that LDL catabolism was subnormal and this was the cause of the raised cholesterol in these subjects. Ciprofibrate therapy increased the apoLDL fractional catabolic rate (FCR) by 19%, principally by inducing a 38% enhancement (P < 0.03) in apoLDL removal by the receptor pathway. ApoLDL kinetics exhibited metabolic heterogeneity both before and during drug therapy. Analysis of plasma decay curves for the LDL tracer and urinary excretion data indicated that the lipoprotein comprised two metabolically distinct species, one with an FCR of about 0.50 pools/day (Pool A), the other with an FCR of about 0.18 pools/day (Pool B). Drug therapy decreased synthesis of and hence reduced the plasma mass of apoLDL in the slow metabolised pool B. This perturbation in synthesis was linked to the change in plasma triglyceride concentration. The resultant reduced proportion of pool B vs. pool A material accounted for the observed promotion of LDL receptor-mediated clearance. Ciprofibrate, therefore, produced beneficial changes in the plasma levels of VLDL, LDL and HDL and in the metabolism of LDL.

Impotence in patients treated with clofibrate.

Three of our regularly controlled patients suffering from Type IV hyperlipoproteinemia and treated with clofibrate complained of impotence within one year after commencement of treatment with this drug. Two of the patients had previously suffered from myocardial infarction. Two patients observed improvement of the symptom 3 and 4 weeks after interruption of clofibrate therapy; one patient again complained of impotence when clofibrate therapy was resumed. The third patient continued intake of the drug up to the present day, and still complains of impotence.

Dose-response effect of single and combined clofibrate (Atromidin) and niceritrol (Perycit) treatment on serum lipids and lipoproteins in type II hyperlipoproteinaemia.

The dose-response effects of clofibrate and niceritrol on serum cholesterol and triglycerides (TG) were studied in 29 patients with Type IIa and IIb hyperlipoproteinaemia. In 17 patients, clofibrate and niceritrol were then given as combined treatment, and the effects of this combination on serum lipoproteins were studied. Clofibrate was given in three doses: 1.5,2 and 2.5 g/day. The optimum effect on serum TG and cholesterol in patients with Type IIa was observed with the 1.5 g dose and higher doses did not lower the serum lipids further. In patients with Type IIb the optimal clofibrate dose was 1.5-2 g/day. Niceritrol was then given in three doses: 3,45 and 6 g/day. In patients with Type IIa the serum TG concentration was not significantly affected by any dose used, whereas the reduction of the serum cholesterol concentration was dose dependent. In patients with Type IIb the reduction of both serum TG and cholesterol was dose dependent. Combined treatment with 2 g clofibrate and 3 g niceritrol resulted in a normal lipoprotein pattern i 15 out of 17 patients. The reduction of the serum lipids was approximately the same as during treatment with 6 g niceritrol/day. No additional side-effects were observed during combined treatment.

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

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

Fenofibrate therapy of hyperlipoproteinaemia. A dose-response study and a comparison with clofibrate.

Fenofibrate is an efficient serum lipid-lowering drug with few clinical side effects. The drug was further evaluated in a study comprising 56 patients, which combined a dose-response trial with a subsequent comparison between the optimal fenofibrate dose and a clofibrate dose of 2 g/day. When the fenofibrate dose was gradually increased (200-300-400 mg/day), a reduction of the elevated lipoproteins within each type of hyperlipoproteinaemia was found. During the dose-response part of the therapy a transient serum creatinine rise was observed, which disappeared at the 400 mg/day level. The highest dose, 400 mg/day, proved to have the best lipid-lower effects. On this therapy the elevated LDL-cholesterol fell by 28% in type IIA + B patients, and the elevated VLDL-TG by 65% in type IIB + IV patients. The HDL/VLDL + LDL-cholesterol ratio increased significantly in all groups, in particular in type IV patients (from 0.19 to 0.28, P less than 0.001). Fenofibrate and clofibrate were each given for 2 months in random order, and the effects on lipoproteins compared. Significant differences were: higher HDL-cholesterol in type IIA on clofibrate, lower LDL-cholesterol in type IIB on fenofibrate, lower TG and cholesterol in both VLDL an LDL in type IV on fenofibrate, combined with higher HDL-cholesterol on this drug. Thus, fenofibrate seems to be an efficient lipid lowering drug with 400 mg/day as an optimal dosage under our conditions.

Comparative toxicity and safety profile of fenofibrate and other fibric acid derivatives.

It is estimated that there are approximately six million patient-years of clinical experience with fenofibrate among physicians outside of the United States. A review of the European literature and unpublished studies supplied by the manufacturer (Laboratoires Fournier, Dijon, France) has been compiled with the data recently reported from a double-blind, placebo-controlled study completed in the United States. In general, fenofibrate has been found to reduce serum triglyceride levels by 30 to 60 percent in patients with type II B and IV hyperlipoproteinemia. Serum cholesterol levels were also reduced by 20 to 25 percent in this group of hypertriglyceridemic patients. A similar reduction in serum cholesterol levels was also found in type II A patients (normal triglyceride levels). Low-density lipoprotein levels were usually reduced in those patients with elevated levels and high-density lipoprotein levels increased when baseline levels were low. Fenofibrate also produced a 10 to 28 percent reduction in uric acid that was sustained for years. The incidence of unwanted effects ranged from 2 to 15 percent in the open trials lasting from a few months up to six years. Gastrointestinal problems (abdominal discomfort, diarrhea, and constipation) are most common, occurring in approximately 5 percent of patients. Reports including fatigue, headache, loss of libido, impotence, dizziness, and insomnia were grouped as neurologic and occurred with a total incidence of 3 to 4 percent. In about 1 percent of patients, muscle tenderness developed, often accompanied by elevated creatine phosphokinase levels. These and the gastrointestinal problems occurred with a similar frequency in the placebo-treated cohort in controlled studies. In approximately 2 percent of patients, a skin rash developed, an incidence that appears significantly higher than that of placebo control groups. Liver changes in rodents have included marked peroxisome proliferation and increased hepatic carcinomas with very high doses. In humans, only a small increase in incidence of elevated levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase seems to be present and is not clearly different from that of the control groups. Alkaline phosphatase, gamma-glutamyl transferase, and bilirubin levels are often decreased with no known undesirable effects. Investigations into the lithogenicity of bile indicated a significant increase in five studies. However, there has been no evidence of a significant rise in the incidence of cholelithiasis in the clinical trials completed to date.