Tolerability of fibric acids. Comparative data and biochemical bases.

Pharmacological Research, Vol . 26, No . 3, 1992

243

TOLERABILITY OF FIBRIC ACIDS . COMPARATIVE DATA AND BIOCHEMICAL BASES CESARE R . SIRTORI, LAURA CALABRESI, JOSE P . WERBA and GUIDO FRANCESCHINI Center E . Grossi Paoletti, Institute of Pharmacological Sciences, University of Milano, via Balzaretti 9, 20133 Milano, Italy Received in final form 8 May 1992

SUMMARY Fibric acids are an established class of drugs for the treatment of hyperlipoproteinaemias . Although they have been in use for 30 years or longer, some doubts remain as to their relative tolerability, both as a class and as single agents . Some side effects, e .g . lithogenicity, may be related to their mode of action, while others, e .g . the acute muscular syndrome, may be linked to the spatial conformation of the molecule . These disadvantages should, however, be weighed against the additional, potentially therapeutic properties shown by these compounds . In particular, effects on maturity onset diabetes and hyperuricaemia, as well as a very interesting fibrinolytic potential, have been described for some of them . A painstaking comparative analysis of the major literature data pertaining to the clinical toxicological profile of these agents allow to conclude that, while belonging to a chemical class, fibric acids show dramatic differences from one another, in terms of side effects and of additional pharmacodynamic activities . Moreover, in the case of lithogenicity for example, considerable differences exist between normo- and hyperlipidaemic subjects . Overall, newer molecules of more sophisticated design have a significantly improved tolerability profile vs the old clofibrate . KEY WORDS :

fibrates, lithogenicity, acute muscular syndrome, diabetes, fibrinolysis .

INTRODUCTION Fibric acids, or 'fibrates', are aryloxyacetic acid derivatives with a potent plasma lipid lowering activity . They are among the most widely used hypolipidaemic agents and one of them, gemfibrozil, has been shown, in a large primary prevention study in moderately hyperlipoproteinaemic subjects, to markedly reduce cardiovascular morbidity and mortality [ 11 . The wide acceptance of these drugs by physicians and patients is, however, still Correspondence to : Prof . Cesare R . Sirtori . 1043-6618/92/070243-18/$08 .00/0

©1992 The Italian Pharmacological Society

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at times hampered by earlier reports of major side effects, particularly encountered during the WHO sponsored study on the primary prevention of coronary heart disease (CHD) with clofibrate [2] . In this study, in fact, the clofibrate treated group showed a high incidence of gallstone disease, gastrointestinal cancer and other, possibly drug related, major side effects . Although similar side effects have never been reported during large scale trials with other fibrates, particularly as indicated by the overall findings in the Helsinki Heart Study with gemfibrozil [1], the question of the tolerability of fibric acids in clinical treatment remains open . The issue is particularly crucial today, when the number of lipid lowering agents has expanded, including some very potent cholesterol lowering drugs [3], thus making a careful analysis of the risk/benefit ratios of major interest to patients and physicians . This review will attempt to analyse in detail the molecular mechanisms whereby fibric acids may affect one or more of the postulated targets of toxicity . Moreover, each specific, real or presumed side effect will be separately evaluated, in order to obtain a comprehensive view of the comparative tolerability of the various agents between themselves and vs the old clofibrate .

FIBRIC ACIDS AND PEROXISOMAL PROLIFERATION : STRUCTURE/ACTIVITY RELATIONSHIP Fibric acids (the major ones are depicted in Fig . 1) may be considered as structural variants of long chain fatty acids, probably exerting their activity by interfering

CH3 CI

O-C-COON

C-NH-CH2-CH2

0 IS 0- CH3 C° OH CH3 CI CI

CH3 Bezafibrate

CN # 0

Ciprofibrate

CH3

CH3

0

O-C-C-O-CH

CI

CH3

CH3

CI

0-C -

0(CH2)3 C -C_ 0H CH3

CH3

Fenofibrate

CH3

CH3

Gemfibrozil

C2H5

101

-0-CH2-CH3

CH3

CI

CH2

O-C-C-0-CA CH3 0

Clofibrate

Fig . 1 .

Beclobrate

Chemical structures of major fibrates .

Pharmacological Research, Vol, 26, No . 3, 1992

24 5

with the fatty acid and, consequently, very low density lipoprotein (VLDL) metabolic cycle . As shown with another fraudulent fatty acid derivative, MEDICA 16 [4] (Fig . 2), the major consequence of fibric acids administration will be a stimulation of the mechanisms whereby the body disposes of excess fatty acids . In particular, at the liver level, /3-oxidation will be stimulated [5] and, at the peripheral tissue level, lipoprotein lipase (LPL) will be activated [6] . These stimulating effects will result in an enhanced catabolism of triglyceride-rich particles, with a more efficient disposal of circulating triglycerides . Species specific responses to this basic mechanism have repeatedly been noted . Particularly in rodents, the increased /3-oxidation of fatty acids is not carried out at the mitochondrial level, as in primates or in humans, but rather at the peroxisomal level, with a consequent proliferation of liver peroxisomes [7] . This may, in turn, result in enhanced carcinogenicity in rodent species [8] . The clinical relevance and potential impact of peroxisomal proliferation for clinical carcinogenicity, although still the object of discussion, has at present led to reassuring conclusions . Peroxisome proliferation could never be clearly shown in man, either because peroxisomes do not proliferate [9] or because this is a non-sustained effect, not correlated with either dosage or treatment efficacy [10] . Evaluation of almost all available fibric acids in a single study on a particularly sensitive rat strain (Fisher rat), exhibiting a limited growth time and thus being particularly sensitive to any `carcinogenic' stimulus, brought the conclusion that second generation fibric acids, in terms of the effective/carcinogenic dose ratio, are safer vs clofibrate [ 1 11 . Liver cell proliferation depends upon an enhanced release of H,O, during peroxisomal /3-oxidation [ 12] . Data from our group and others have shown that the cluster of negative charges on the clofibrate molecule may probably be critical for a more active proliferation of peroxisomes . Substitution of Cl- with F- on the clofibrate molecule (Fig . 3) may result in a reduced peroxisomal proliferation 113] . In one of our studies, it was concluded that the presence of weak electron attractors in the para (p-) position will lead to the maintenance of the aromatic configuration in the substituted ring, and will not result in an enhanced peroxisome formation (Fig . 4), while maintaining the lipid lowering properties [14] . Essentially all newer fibric acids carry a far bulkier p-substituent vs clofibrate (Fig . 1) ; in the case of gemfibrozil, the presence of two -CH 3 groups in

CH3 HOOC-CH2-C-CH2-CH2-CH2-CH2-CH2 CH3 CH3 HOOC-CH2-C-CH2-CH2-CH2-CH2-CH2 CH3

Fig. 2 . Chemical structure of MEDICA 16, a synthetic long chain dioic fatty acid, displaying most of the characteristics of fibrates .

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Pharmacological Research, Vol. 26, No . 3, 1992

CI

CH3 i O-C-COO C2H5

Lipid lowering

Perox . prolifer.

+ + +

+ + +

+++

0

CH3

CH3 O-C-COO C2H5 CH3 Fig . 3. Chemical structure of clofibrate vs peroxisomal proliferatory potential : substitution of the Cl - with F- results in an almost complete loss of proliferatory capacity [10] .

gem configuration on the phenyl ring may also lead to a very weak electron attraction .

MAJOR SIDE EFFECTS OF FIBRIC ACIDS : LESSONS FROM THE CLOFIBRATE STUDIES Long-term studies with clofibrate date back many years . The first studies were published in 1971 and reported the experience of two British groups : physicians from Newcastle upon Tyne [15] and members of the Scottish Society of Physicians [16] . These two cooperative studies followed approximately 1300 male and female patients with a history of CHD for five and six years, respectively . Clofibrate and placebo were administered according to a randomized protocol . The two studies demonstrated that clofibrate treatment can effectively reduce cardiovascular mortality in patients with a history of angina or angina plus myocardial infarction (MI), whereas it is ineffective in patients with a history of MI alone . The correlations between changes in plasma lipids (essentially only cholesterol was measured) and successive cardiovascular mortality were weak . Both these studies reported an extremely low incidence of side effects, occurring in very few cases ; there was one case of reversible alopecia, and no clearcut cases of muscular pain (see below) . A far higher incidence of side effects was instead noted in a later study, comparing clofibrate and nicotinic acid in post-MI patients, known as the Coronary Drug Project [17] . In this, at least seven major side effects were noted in the clofibrate group : (a) a significantly increased incidence of thromboembolism ; (b) an increased number of patients describing new symptoms of angina pectoris ; (c) an increased number of cases with intermittent claudicatio ;


2 47

(d) an increased incidence of gallstones ; (e) an increased incidence of premature ventricular contractions ; (f) an increased number of patients describing loss of libido and/or tension of the mammary glands ; (g) an increased percentage of patients with hepatosplenomegaly . These observations strongly indicate caution in clinical data analysis . Whereas the sexual effects may possibly be linked to an estrogenic action of clofibrate [18] . the others require more careful comment . There is no explanation for the increased incidence of premature ventricular contractions and of angina (in both cases the diagnosis was based on patients' reports) . Actually, when examining the number of patients receiving new treatments during the trial, it could be seen that 47 .6% in the placebo group were given nitroglycerin vs only 42 .4% in the clofibrate group . Another unclear finding is that of the increased incidence of intermittent claudicatio, which contradicts prior reports on the beneficial effects of the drug in patients with peripheral artery disease [191 . Most likely it was secondary to the observation of some cases of myopathy, definitely a rare but significant side effect

BR- 931 Cl

SHcatH-CH 2

BR-971

I '

H

CH2OH

"HH

H

CI --"

hi

H I Y

-CH2-COOC2H5

NH

Cl

N'1

.,S-CH2COHH-CH2 CH2OH

CH3 CH3

H Xyl

Fig . 4 . Possible molecular rearrangements of BR-931, a potent peroxisomal proliferator, and of its analogue BR-971, a non-proliferator . It appears that BR-931 undergoes a rearrangement of the pyrimidine ring, from an aromatic to an aliphatic configuration ; this is apparently linked to the peroxisomal proliferatory potential . This does not occur with BR-971, where the pyrimidine ring maintains the aromatic configuration .

2 48


of the drug [20] . This hypothesis is supported by the elevation of creatine phosphokinase (CPK) activity at the end of the study . Finally, also the increased incidence of thromboembolic episodes is surprising . Since clofibrate and other fibric acids generally seem, if anything, to increase fibrinolytic activity [21], this observation may possibly be the consequence of the frequent hospitalization of treated patients during the trial . The only clearcut and reproducible side effect is probably that of increased gallstone disease, generally confirmed in the major studies with clofibrate . Gallstone disease stands out as the major adverse phenomenon in clofibrate treated patients also in the WHO sponsored study in Edinburgh, Budapest and Prague [2] . During this trial, out of 5331 hyperlipidaemic patients treated with clofibrate, 59 underwent a cholecystectomy, vs 24 in the high-cholesterol placebo group and 25 in the low-cholesterol control group . Analysis of the data shows clearly a higher incidence of disease during the first two years of clofibrate treatment (11 cases in the clofibrate vs respectively two and five in the highcholesterol placebo and low-cholesterol control groups) . Of course, the WHO study brought to light other disquieting abnormalities, particularly a high incidence of malignant neoplasma in the gastrointestinal system and the lung, which, although not reaching statistical significance (40 cases in the clofibrate vs 24 in the high-cholesterol placebo and 30 in the low-cholesterol control groups) was certainly a factor in the ensuing loss of popularity of clofibrate . Surprisingly, other previously noted side effects did not appear to have a significant impact in the WHO study . Only weight gain and an unclear high incidence of diabetes and hyperhidrosis (in Edinburgh) were apparently related to clofibrate treatment . Muscular fatigue and cramps, although with a higher incidence in the clofibrate group, did not differ significantly vs the highcholesterol placebo and the low-cholesterol control groups .

GALLSTONE DISEASE AND FIBRIC ACID TREATMENT : COMPARATIVE DATA Cholesterol gallstones are a very frequent observation in the middle aged populations in Western Europe . They are more frequent in women, and oestrogens are believed to be an important factor in the formation of gallstones [22] . While the presence of gallstones is extremely frequent (from 10 to 20% of the adult population), symptomatic gallstone disease is rare, probably occurring in not more than 22% of gallstone carriers [23] . The bile of gallstone subjects is generally supersaturated with cholesterol, i .e . containing more cholesterol than can be solubilized by the available bile acids and phospholipids [24] . While supersaturated bile is a necessary metabolic prerequisite for the development of cholesterol gallstones, their actual formation requires bile nucleation and growth of cholesterol crystals [25] . Administration of clofibrate always increases biliary cholesterol secretion and faecal excretion of neutral sterols ; there is also evidence of a decrease in bile acid synthesis [26] . This is true both for type IV patients, who show disproportionately high cholesterol synthesis and elimination [27], as well as for type II patients .


249

After long-term treatment, plasma cholesterol radioactivity decay curves indicate that cholesterol synthesis and cholesterol pools are significantly reduced [28], the decrease of cholesterol in total body pools frequently far exceeding that of cholesterolaemia [29] . Although the mechanism for the increased secretion of cholesterol into bile is unknown, it may be noted that administration of a primary bile acid, chenodeoxycholic acid, leads to a marked reduction in the bile saturation index and also strikingly reduces cholesterol secretion into bile, thus suggesting that the primary mode of action of clofibrate might be by reducing bile acid secretion [30] . Stimulation of bile acid synthesis by cholestyramine appears to prevent the lithogenic effect of clofibrate [31 ] . Any comparative evaluation of the lithogenic potential of different drugs should take into account : (I) bile cholesterol supersaturation ; (2) the bile acid pool size, in view of the well demonstrated lithogenicity of a low bile acid output [32] ; (3) the possible intervention of anti-lithogenic, most likely anti-nucleation factors [25] . Moreover, in the special case of a lipid-lowering treatment, a possible difference in sensitivity between normolipidaemic and hyperlipidaemic individuals should be considered . Studies investigating the potential lithogenicity of the different fibric acid derivatives have evaluated : (a) short- vs long-term administration ; (b) direct comparisons between different fibric acids (short-term) ; (c) evaluation of the lithogenicity in normolipidaemic and hyperlipidaemic conditions . The possibility that bile lithogenicity may vary, and probably decrease upon long-term administration is suggested by the mode of action of these agents . In

fact, if a major mechanism of fibric acids is linked to a progressive reduction of body cholesterol pools, it may be inferred that prolonged administration will lead to a new steady-state, thus eventually bringing saturation indexes to pre-treatment levels . Studies in short- vs long-term administrations of clofibrate in hyperlipoproteinaemic patients led to the expected increase (+50%) of the saturation index after six months ; this elevation was not dramatically changed after two years (+45%), except for the observation of a return toward normal levels in two out of nine patients [33] . A similar study with bezafibrate showed a lesser increase in the saturation index (+18%) at four weeks, and this was sustained after one year of treatment (+19%) ; in this case five out of 12 patients tended to return to a normal biliary composition [34] . Therefore, apparently the effect of fibric acids on biliary composition is sustained ; however bezafibrate, in similar conditions, is less lithogenic than clofibrate and the likelihood of a return toward a normal biliary composition is higher . An interesting comparison is that of normo- vs hyperlipidaemic individuals in terms of the lithogenic response . It has been repeatedly stated that type IV patients show an increased bile cholesterol saturation, possibly consequent to a defective

250


recirculation of primary bile acids, particularly cholic acid [35] . All studies where clofibrate lithogenicity was tested in normolipidaemic subjects provide essentially equivalent data vs studies carried out in hyperlipidaemics . Increases in the saturation index were between 14 and 30% in normolipidaemics [36, 37], vs 14 and 34% in hyperlipidaemics [33, 38] . Similar findings were obtained with fenofibrate : upon short-term administration, the saturation index rose 11% in normolipidaemics [36] and 14-35% in hyperlipoproteinaemics [39, 40] . Bile hypersaturation with this drug is an inconstant finding, according to one series of examined patients [41] . Significant differences in the response between normo- and hyperlipoproteinaemic subjects were instead noted after bezafibrate administration . In this case, in fact, normolipidaemic subjects were characterized by a complete lack of response to the agent [42] ; neither the saturation index, nor the concentrations of the single biliary components, cholesterol, phospholipids and bile acids, appeared to be affected by treatment . Instead, in hyperlipoproteinaemic patients, the saturation index increased between 18 and 26% [34, 43] with, as indicated, minor differences between short- and long-term administrations . In the case of gemfibrozil, only one study examined hyperlipidaemic patients . Interestingly, this was a cross-over (six weeks) study vs clofibrate : whereas clofibrate administration led to the expected rise in the saturation index (+12%), gemfibrozil treatment was actually accompanied by a reduction in the same parameter [38] . With the same drug, instead, data were widely divergent when examining normolipidaemic volunteers . In an earlier single blind cross-over study vs clofibrate, gemfibrozil led to a far lower increase of cholesterol excretion vs the reference compound [37] ; these same findings were confirmed by a similar study [38], again in normolipidaemic individuals . In contrast, Leiss et al . [44] detected a remarkable increase in bile lithogenicity (after three months of treatment) ; by examining both gallbladder and hepatic bile, they noted an increased output of cholesterol (+49%) and decreased output of bile acids (-26%) with unaltered phospholipid concentrations ; chenodeoxycholic acid secretion decreased significantly without changes in cholic acid . Etofibrate was the object of only one study, where it was compared with other fibric acids, and resulted in a 24% rise of the lithogenic index in healthy volunteers [36] . Finally, the only fibric acid apparently not changing biliary lipid composition is ciprofibrate [45], albeit in only one study . After six weeks of treatment with 100 mg/day there was no change in the cholesterol saturation index (in spite of a small reduction of bile acid secretion) ; the same findings were noted after one year of treatment in 10 of the treated patients, where the saturation index went back to below pre-treatment levels . Only one study is available on beclobrate, in hyperlipidaemic patients, showing a 36% rise (non-significant) in the cholesterol saturation index [46] . In summary, it appears that all fibric acids, with the exception of ciprofibrate, show a lithogenic potential (Table I) . This is, in general, lower than that of clofibrate . The comparative studies, in the same individuals, of clofibrate vs gemfibrozil consistently indicate a lower cholesterol output with gemfibrozil [37, 38] . Interestingly, whereas bile supersaturation remains stable with prolonged treatment in most patients on clofibrate, this is far less clear in the one study, with


25 1

bezafibrate, examining biliary compositional data following short- and long-term administration of the drug [34] . These data certainly do not fully explain why during gemfibrozil treatment in the Helsinki Heart Study there was essentially no change in the number of cholecystectomies (12 in the 2030 placebo vs 18 in the 2051 gemfibrozil individuals) over five years [1] . Moreover, in this study there was no clear sign of an acceleration of gallstone disease, as shown-in the WHO study with clofibrate [2] . These observations suggest that, in addition to probably eliciting a lesser increase in bilary cholesterol saturation, the newer fibric acids may be more likely to show a reversible hypersaturation [34] . These differences may also be explained by an as yet unexplored activity of newer fibric acids on anti-nucleation factors . Recent data suggest that apolipoproteins A-I and A-I1 in supersaturated model bile may effectively prolong the nucleation time of cholesterol monohydrate crystals [47] . If, as repeatedly indicated, biliary output is prevalently reduced during the night time [48], then changes leading to an enhanced excretion of these apolipoproteins into bile may possibly counteract the critical time of gallstone formation in exposed patients . Altogether, however, the major mode of action of fibric acids, i .e . mobilizing cholesterol and transiently or permanently raising cholesterol saturation in bile, should not differ dramatically between the various fibric acids . The very clear evidence of a different risk for gallstone formation is, therefore, attributable to the milder effects on cholesterol excretion/bile acid production and, likely, also to some anti-nucleation activity, apolipoprotein related or not, characteristic of the various agents and still needing complete elucidation .

FIBRIC ACIDS AND ACUTE MUSCULAR SYNDROME An acute muscular syndrome was described very early after the introduction of clofibrate into clinical therapy [20] . The five initially described cases, on standard doses of clofibrate, all exhibited a marked elevation of CPK activity, but only one case had symptomatic myalgia . All had some elevation of serum transaminase

Table I Fibric acid derivatives : effects on bile cholesterol saturation in normoand hyperlipidaemic subjects Normolipidaemics (%)

Clofibrate Beclobrate Bezafibrate Ciprofibrate Fenofibrate Gemfibrozil NC : no change . ND : not determined .

+14-30 ND NC ND

+11 +9-73

Hyperlipidaemias

(%) +14-34 +36 +18-26 NC +14-35 -6

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levels . Interestingly, in none of the major secondary or primary prevention trials with clofibrate (Newcastle upon Tyne, Scottish Society of Physicians, CDP and also in the WHO Study) was acute muscular syndrome or even myalgia consistently noted (see above) . Muscular fatigue was somewhat more frequent in the clofibrate treated subjects during the WHO study (seven reports vs two and three in the placebo and low-cholesterol control groups), but statistical significance was not reached and there was no laboratory assessment of the condition [2] . More recently, a case of generalized muscle pain and weakness, with electron microscopic changes indicative of atrophy of some muscle fibres was described [49] . In this report, an interesting overview of 44 other literature cases of acute muscular syndrome is provided ; out of these, 27 were in patients with moderate to severe renal failure, thus suggesting that defective clofibrate excretion is probably a factor in the induction of the syndrome . In six patients serum levels of clofibrate were measured and found to be in the high-toxic range ; five of these were continued on clofibrate at a lower dosage and all recovered . Two major hypotheses have been raised to explain this toxic effect of clofibrate . The first one relates to the possibility, as seen in rats, that a `myotonia' may develop due to an accumulation of cholesterol precursors, particularly 20,25diazacholesterol [50] . However, a characteristic myotonia, with muscle stiffness and delayed muscular relaxation was achieved in rats, without any accumulation of 20,25-diazacholesterol in serum [51] . The second hypothesis links muscle toxicity to impaired chloride channel function in muscle fibres . This effect is exerted only by achiral clofibric acid and by the S-(-) isomers, not by the R-(+) propionic and butyric acid isomers [52], suggesting that specific enantiomers may interact with the chloride channel receptor [53] . There are essentially no reports on acute muscular syndromes with the newer fibric acids . It is remarkable that during the Helsinki study, myalgia or muscle pain were never described [1] . Since the chloride channel blocking effect appears to be dependent upon the steric conformation of the butyric/propionic acid side chain of clofibrate derivatives, the compounds with longer side chains, e .g . gemfibrozil, will probably not show such an effect . It is also possible that the presence of additional rings, e .g . in beclobrate, bezafibrate and fenofibrate, will also alter the interaction of the short side chains with the chloride receptor . In a few studies, CPK levels were monitored during treatment with the different fibric acids . The only marked rise occurred in dialysis patients, where gemfibrozil raised CPK levels by 300% [54] ; another smaller study on similar patients showed a 69% increase of CPK [55] . The drug was not associated with changes of this parameter in any report on subjects with a normal kidney function . While neither for beclobrate nor for ciprofibrate are there any reports of transient or permanent changes of CPK levels, one study suggests a 28% rise of the enzyme in fenofibrate treated patients [56] . Finally, a mean rise of 50% of CPK levels is reported with bezafibrate in only one study [57] . The inconsistency of these observations casts doubts on their real clinical significance . This may also be an important difference when comparing these drugs with HMG-CoA reductase inhibitors [58] . Such a conclusion should, of course, not delete warnings on the potential adjunct muscular toxicity of reductase inhibitors and fibric acids, when used in combined


253

treatments, although the reports are only limited to gemfibrozil plus lovastatin [59] .

FIBRIC ACIDS AND LIVER TOXICITY In view of the clear activity of fibric acids at the liver level, and also in view of the extensive handling of these compounds by the liver (Table II), the possibility of a more or less marked liver toxicity is underlined in most reviews on these agents . When examining the activity of the different fibric acids on the standard liver toxicity tests, e .g . transaminases, bilirubin, alkaline phosphatase, ),,-glutamyl transpeptidase (y-GT) and lactate dehydrogenase (LDH), the data are generally inconsistent and do not provide an indication for a direct potential of these drugs to alter liver function . As summarized in Table III, data on clofibrate from at least five studies do not indicate any significant change in transaminases, while drug GT bilirubin and alkaline ) treatment is associated with a reduction in , phosphatase levels . This last finding is typical of all fibric acids, with the

Table II Fibric acid derivatives : major metabolic and kinetic parameters Absorption (%)

Protein binding (%)

Metabolism

Renal elimination

t ; (h)

Clofibrate

99

97

De-ethylation Minor metabolite formation conjugated with glucuronide

15-22

Bezafibrate

95

94-96

50% unchanged 22% glucuronide conjugates 22% other polar metabolites (hydroxy and others)

3-9

Fenofibrate

90

99

De-ethylation 50% conjugated 50% polar metabolites (phenol, benzhydrol)

20-26

Gemfibrozil

90

95

40% unchanged 60% numerous metabolites (conjugated, benzoic acid, phenol, etc .)

2-3*

Ciprofibrate

90

90

De-ethylation 70% glucuronide conjugates

42

Beclobrate

90

90

De-ethylation Glucuronides of beclobric acid and of oxidative metabolites

15-18

*For the unchanged drug .

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Table III Fibric acid derivatives : major changes in liver toxicity parameters Alkaline phosphatase (%)

Clofibrate Bezafibrate Fenofibrate Gemfibrozil Ciprofibrate

GOT (%)

-25 -26 -25

-35

GPT (%)

)I-GT (%)

Bilirubin (%)

-47

-47

-29

+26

+45

exception of gemfibrozil, for which, out of at least six studies, none showed a change of alkaline phosphatase [60] . The reduction of alkaline phosphatase is apparently linked to an effect on the intestinal fraction of the enzyme, previously shown to lead to an enhanced thrombogenesis in experimental animals [61 ] . It has also been proposed that the distribution of alkaline phosphatase fractions in man is related to the ABO blood group secretory status [62] ; a relationship between secretory status and serum cholesterol changes in rats in response to different diets has been suggested by Benton et al . [63] . Interestingly, in two studies with two different fibric acids, ABO secretors consistently had a significantly different hypocholesterolaemic response following drug treatment vs non secretors [64, 65] . Although there are no data from comparative studies with the different fibric acids, it can be reasonably concluded that, in addition to clofibrate, also bezafibrate and gemfibrozil have absolutely no activity on the major parameters of liver toxicology . In the case of ciprofibrate, instead, rises in GOT of 24 and 28% and in GPT of 41 and 49% occurred after six and nine months of treatment [66, 67] ; however, none of these changes reached statistical significance . There is, therefore, no clear evidence that any of the new fibric acids is significantly hepatotoxic in man, at least based on the standard liver function tests . The observed abnormalities, if any, do not appear to be correlated to the length of treatment . Changes in alkaline phosphatase are generally in the opposite direction as would be expected in the case of bile stasis .

CHANGES IN OTHER LABORATORY TESTS In none of the studies with fibric acids was there any significant change of the major kidney function parameters, i .e . urea and creatinine ; these compounds also did not affect to any extent the electrolyte patterns . Of particular interest are instead possible metabolic changes (outside of lipids) occurring with some of these agents . In the case of diabetes, there have been several reports suggesting a potential therapeutic use . Initial reports on clofibrate provided evidence of a reduced insulin resistance [68], as well as of a reduced insulin/glucagon ratio [69] after treatment . There appear to be no significant effects on glucose metabolism with the other fibric acids, except for two reports,


25 5

suggesting that both bezafibrate and gemfibrozil can reduce fasting glucose levels in diabetics [70, 711 . Fenofibrate is apparently endowed with an unusual, highly significant activity on uric acid levels [72], not shared by the other agents . The fenofibrate activity is directly consequent to a uricosuric effect, probenecid like [73], potentially very useful in subjects with multiple metabolic abnormalities . EFFECTS OF FIBRIC ACIDS ON COAGULATION AND FIBRINOLYSIS Different effects have been reported with the various fibric acids on the major clotting parameters, particularly fibrinogen, platelet aggregation and fibrinolytic activity . Fibrinogen, now rated as a major independent risk factor for cardiovascular diseases [74], is reduced by most agents, i .e . the old clofibrate, as well as bezafibrate and ciprofibrate . The fibrinogen reductions with these drugs range between a minimum of 10% to a maximum (with bezafibrate) of 45% in hyperfibrinogenemic patients [75] . No clear data are available on fenofibrate and beclobrate, whereas with gemfibrozil, out of four studies reporting fibrinogen levels, three did not show any change whereas in one [60], a 10% rise is described . Platelet aggregation was inconsistently monitored following treatment with the different fibric acids, Earlier studies with clofibrate showed reduced platelet sensitivity to aggregating agents, both ex vivo and after adding. the drug to an in vitro system [76] ; the aggregation changes were apparently associated with a reduced platelet turnover [77] . In the quoted study on hyperfibrinogenaemic patients, Pagano et al . [75] reported a reduced platelet aggregability after bezafibrate . With gemfibrozil, scattered reports failed to show any significant change of platelet aggregation/eicosanoid metabolism ; in a study by our group . gemfibrozil treatment only somewhat reduced thromboxane B2 release from platelets of hypertriglyceridaemic patients [78] . In the case of fenofibrate, one study [79] showed a return to normal from previous hyperaggregability of platelets from type IIB patients . No clearcut data are reported with beclobrate ; in one study with ciprofibrate [80], again no definite changes are described . Finally, etofibrate, sharing the properties of both nicotinic acid and of fibrates, reportedly increases the prostacyclin/thromboxane ratio in the plasma of type II patients [81 ] . Interest in fibrinolytic activity is particularly high today, when increased levels of a direct inhibitor of fibrinolysis have been reported in type IV patients [82] . Unfortunately, clearcut data related to the effect of fibric acids on this parameter are definitely lacking, since in no one study has an adequate evaluation of fibrinolytic agonist (tPA) and antagonist (PAI-1) levels, both in terms of mass and of activity, been carried out . Although occasional reports [80] show increases in global fibrinolysis with some of these agents, more extensive and detailed data are expected before drawing definitive conclusions . CONCLUSIONS An evaluation of the tolerability of different fibric acids clearly shows that these

25 6


drugs should not be grouped under a single heading . They differ strikingly in their structure/activity relationship, metabolism/distribution, potency and finally, pattern of additional effects, either wanted or unwanted . It may be generally concluded that newer agents, because of their more advanced chemical design, are weaker electron attractors on the phenyl ring, thus eliciting a low tissue reactivity vs the old clofibrate . This may explain the low inducive potential on liver peroxisomes . In addition, biliary studies show that the new drugs mostly induce a reduced or negligible cholesterol saturation and that often this may be reversible upon long-term treatment . Whether the more marked lipoprotein changes (increased apolipoproteins A-I and A-II) occurring with the newer fibric acids may also explain the lower incidence of gallstone disease has yet to be established . Of special interest is the very low risk of muscle abnormalities with the second generation fibrates, both vs clofibrate and, in all likelihood, vs the HMG-CoA reductase inhibitors . A direct liver toxicity, similarly, is probably an irrelevant side effect of newer agents . Finally, the remarkably divergent activities on clotting parameters, both in terms of fibrinogen levels, platelet aggregation and fibrinolysis, may underline the widely different pharmacodynamic (in addition to pharmacokinetic) profile of fibric acids . It appears, therefore, a gross oversimplification to group fibric acids as just one series of clofibrate analogues . Also when leaving aside the clear differences in the activity profile vs lipids/lipoproteins, these compounds should be considered as individual molecules which, although probably acting via a common mechanism on lipoprotein metabolism [6], do exert different effects on other parameters of body homeostasis, the overall tolerability being generally good .

ACKNOWLEDGEMENTS The expert assistance of Dr Roberto Nebuloni in the retrieval of bibliographic data is gratefully acknowledged .

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Data compression of large document data bases.

Information data bases.

Searching publication data bases.

From data banks to data bases.

Organic acids and bases: review of toxicological studies.

[Injuries caused by acids and bases - emergency treatment].

Hydrogen bonding between nucleic acid bases and carboxylic acids.

SDC experiences with large data bases.

Hydration of DNA bases: analysis of crystallographic data.

Chemical Abstracts Service approach to management of large data bases.

Static and dynamic properties of 1,1'-bi-2-naphthol and its conjugated acids and bases.

Predicting the pKa and stability of organic acids and bases at an oil-water interface.

Intracellular pH and the distribution of weak acids and bases in isolated rat superior cervical ganglia.

What indication is common to different genotoxicity data bases?

Integrity of small data bases in computer analysis of dietary data.

General analytical procedure for determination of acidity parameters of weak acids and bases.

Unravelling the surface chemistry of metal oxide nanocrystals, the role of acids and bases.

Triplet excited state of furocoumarins: reaction with nucleic acid bases and amino acids.

Effects of Acids, Bases, and Heteroatoms on Proximal Radial Distribution Functions for Proteins.

Singlet energy transfer between aromatic amino acids and nucleic acid bases. Theoretical calculations.

Screening nitrogen-rich bases and oxygen-rich acids by theoretical calculations for forming highly stable salts.

Ocular Tolerability of Preservative-Free Tafluprost and Latanoprost: in vitro and in vivo Comparative Study.

Comparative efficacy and tolerability of topical prostaglandin analogues for primary open-angle glaucoma and ocular hypertension.

Regulation of gene expression by fatty acids and fibric acid derivatives: an integrative role for peroxisome proliferator activated receptors. The Belgian Endocrine Society Lecture 1992.