Drug interactions with fibric acids

~ ) Pergamon 0163-7258(94)EOO27-Y Pharmac. Ther. Vol. 63, pp. 163-176. 1994

Copyright ~. 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved

0163-7258/94 $26.00

Specialist Subject Editor: C. R. SIRTORI

D R U G INTERACTIONS WITH FIBRIC ACIDS

ALFREDO LOZADA a n d CARLOS A. DUJOVNE*

Lipid and Arteriosclerosis Prevention Clinic, Division of Clinical Pharmacology, University of Kansas Medical Center, 1348 KU Hospital, 3901 Rainbow Boulevard,

Kansas City, KS 66160-7374, U.S.A.

Abstract--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.

Keywords--Bezafibrate, clofibrate, dislipidemia, drug interactions, fenofibrate, fibratcs, fibric acid derivatives, gemfibrozil, lipid-drug interactions.

CONTENTS

I. General Pharmacology and Therapeutic Effects of Fibric Acids 164 I.I. Therapeutic uses and potential drug interactions of fibrates 165

2. Clofibrate 165 2.1. General pharmacology and therapeutic effects 165 2.2. Pharmacokinetic interactions 166

2.2.1. Anticoagulants 166 2.2.2. Antidiabetics 167 2.2.3. Interactions with other drugs 167

2.3. Pharmacodynamic drug interactions 169 2.3.1. Oral contraceptives 169 2.3.2. Probucol 169

3. Gemfibrozil 170 3.1. General pharmacology and therapeutic effects 170 3.2. Pharmacokinetic drug interactions 170

3.2.1. Anticoagulants 170 3.2.2. Antidiabetics 170 3.2.3. Interactions with other drugs 170 3.2.4. On the issue of myopathy potentiation between gemfibrozil and lovastatin 172

3.3. Pharmacodynamic drug interactions 172 4. Fenofibrate 173 5. Ciprofibrate 173 6. Bezafibrate 173 References 174

*Corresponding author. Abbreviations--CPK, creatinine phosphokinase; HDLC, high density lipoprotein cholesterol:

density lipoprotein cholesterol; VLDL, very low density lipoprotein.

JPI 63 2-~. 163

LDLC, low

164 A. LOZAOA and C. A. DUJOVNE

1. GENERAL PHARMACOLOGY AND THERAPEUTIC EFFECTS OF FIBRIC ACIDS

Fibric acid is the parent compound of clofibrate, gemfibrozil (currently the most prescribed fibrate drug in the United States), and several derivatives marketed only outside the United States, such as the drugs bezafibrate, etofibrate, ciprofibrate and clinofibrate. Fenofibrate has just been approved by the United States Food and Drug Administration. In Europe, all fibratc drugs combined are prescribed more often than any other type of lipid-acting drugs, including the newest inhibitors of hydroxy-methylglutaryl coenzyme A reductase (statins).

One of the most important therapeutic actions of fibrates is decreasing the production of very low density lipoprotein (VDL) cholesterol by the liver, resulting in the lowering of serum triglycrides levels, This triglyceride-lowering effect is also produced by their capacity to stimulate lipoprotein lipase activity in plasma and in adipose tissue. The catabolism of VLDL cholesterol, therefore, is stimulated, inducing a consequent decrease in V L D L cholesterol triglycerides and in VLDL cholesterol apo B (Schwandt, 1991).

These effects on VLDL cholesterol metabolism may be produced by the "fraudulent fatty acid mechanism" by which the fibric acid may stimulate the disposal of excess fatty acid, with an increase in hepatic beta oxidation and also an enhanced activity of lipoprotein lipase. These effects will increase the disposal of circulating triglycerides (Sirtori et al,, 1992).

The chemical structures of fibrates are shown in Fig. ! (Sirtori et al., 1992). These drugs are aryloxyacetic acid derivatives that may exert their activity by means of a fraudulent fatty acid mechanism, since they can be regarded as structural variants of long-chain fatty acids.

The dyslipidemias in which fibrates are more commonly used are the types IV and lib (World Health Organization Classification); they produce significant decreases in serum triglycerides, and can also increase or decrease the levels of L D L cholesterol (LDLC). In type IIA, another very prevalent dyslipidemia manifested by an increase in total cholesterol and LDLC, fibrates usually produce only modest decreases in total cholesterol and in LDLC. Some of the newer fibric acids produce greater reductions in LDLC than chofibrate does (Hunninghake and Peters, 1987).

Fibrates are the most effective drugs for treatment of the more rare type 1II disorder (increased floating B lipoprotein). The main therapeutic effect of fibrates is decreasing serum triglyceridc levels, which is usually accompanied by an increase in high density lipoprotein cholesterol (HDLC). Increases in HDLC levels may also occur independently when fibrates are administered to normo-triglyceridemic dyslipidemics with hypoalphalipoproteinemia.

Fibric acids may also have an effect on reducing serum LDLC levels, but this effect is usually of smaller magnitude and less predictable than with other lipid-acting drugs, This effect might be related to inhibition of hepatic hydroxy-methylglutaryl coenzyme A reductase, but the mechanism is still unclear.

o c,3 c,3 o 0o- , - oo,

CH3 CI CI CN3

Bezafibrate Ciprofibrate

0 CH 3 0 CH 3 ~ C H 3 CH3

CH 3 CH3 £H 3 CH3

Fenof i bra te Gem f i broz i l

c1 o ,c2,s c-o-c,rc,3 cl c-c-o-c2, CH 3 CH 3 0

Clofibrote Beclof i brote

FIG. 1. Chemical structures of major tibrates.

Drug interactions with fibric acids 165

In one of the largest primary prevention clinical trials ever conducted with fibric acid derivates (the Helsinki Heart Study) a significant increase in HDLC was observed in those patients taking gemfibrozil, and the increases were more evident in the subgroup of patients with type IIb disorder (Frick et al. , 1987).

The interactions of fibrates with other drugs are clinically relevant, and the pharmacological properties and other effects of these drugs that are relevant to their potential for drug interactions are: (a) a very high binding affinity to plasma proteins, especially albumin; (b) changes 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 (Gibson et al. , 1982; Fournel et al. , 1983).

The fibric acids are utilized, often for a lifetime, in patients with dyslipidemia, who frequently have other diseases that may require other drugs. Fibrates may be used concomitantly with other highly protein-bound drugs with narrow therapeutic windows, such as oral hypoglycemics, anticoagulants and phenytoin. Adverse reactions may occur when the ratio of free to bound drug increases due to displacement by fibrates of the respective drugs from their serum-protein binding sites during concomitant administration.

Other drugs that are not highly protein-bound may interact with fibrates by other mechanisms. Some of these other mechanisms of potential drug interaction are the induction of the hepatic cytochrome P450, which may increase the metabolism of drugs, and the induction of cytochromes P450 IVAI and IVA3, which may alter the metabolism of exogenous and endogenous compounds, such as fatty acids and prostaglandins (Aoyama et al., 1990; Gibson et al. , 1982).

l . l , THERAPEUTIC USES AND POTENTIAL DRUG INTERACTIONS OF FIBRATES

Fibric acid derivatives are most often utilized for the treatment of patients with primary lipid disorders, but are also used to treat dyslipidemia secondary to diabetes mellitus, hence their potential for more frequent interactions with antidiabetic drugs.

Patients with elevated serum cholesterol and/or triglycerides levels may have severe atherosclerotic cardiovascular disease. Consequently, some of these patients might be receiving one or other drug for the therapy of those concomitant atherosclerotic cardiovascular disease conditions; many of these drugs, that is anticoagulants, antiarrythmics or antihypertensives, can be displaced from their protein binding sites, and the consequent variability in free-drug levels offers great potential for changes in the extent of pharmacological and/or side effects. For instance, coadministration of clofibrate or halefenate (an experimental fibrate derivative) with propranolol may lead to changes in the extent of fl-adrenergic receptor blockade produced by propanolol (Huffman et al. , 1976).

In order to facilitate the review of the interactions of the fibric acid derivatives with other types of drugs, we will describe the interactions of each fibrate drug separately. We will also describe separately the type of interactions produced by pharmacokinetic changes (what biological functions of the body do to the disposition of the drug) from those that are produced by pharmacodynamic changes (what the drug does to the body's biological functions and parameters).

2. CLOFIBRATE

2. I. GENERAL PHARMACOLOGY AND THERAPEUTIC EFFECTS

As mentioned in Section i, clofibrate is an acidic drug, the chemical structure of which is shown in Fig. i. After an almost complete absorption, clofibrate is hydrolyzed by serum enzymes to the pharmacologically active drug chlorophenoxyisobutyric acid or clofibric acid.

It is distributed mainly in the extracellular space and, therefore, has a relatively small volume of distribution of approximately 7 L. It binds extensively to serum proteins (96%), especially to albumin (Inoue et al. , 1980).

After its initial hydrolysis, clofibric acid is conjugated to glycoronic acid in the liver and eliminated mainly by the kidney, 60% as a glucoronide and the rest as clofibric acid and other

166 A. LOZADA and C. A. DUJOVNE

minor metabolites. It has a non-linear excretion with a long and variable half-life of 6-25 hr, which can be markedly increased in renal failure.

Clofibrate and other fibrates may produce changes in the activity of drug-metabolizing enzymes in the liver microsomes, and this can be relevant to the potential consequences of the concomitant administration of drugs that are metabolized by that system.

Clofibrate and other drugs have been reported to produce changes in the liver scan images obtained by radiolabeled technetium, possibly by affecting the activity of the reticuloendothlial system or the hepatosplenic distribution of blood flow (Fournel et al., 1983; Dujovne and Strauss, 1971).

The mechanism of action of clofibrate on lipoprotein regulation is to decrease the production of VLDL cholesterol in the liver and to stimulate the activity of lipoprotein lipase, therefore lowering triglycerides and having the most marked effect on VLDL and intermediate density lipoprotein metabolism. Clofibrate is also effective in mixed (type lib) and other dyslipidemias of types III and IV through this mechanism, as well as other lesser understood mechanisms (Taylor et al., 1977).

2.2. PHARMACOKINETIC INTERA('TIONS

2.2. I. Ant icoagulants

There have been many contradictory reports on the type of interactions between fibrates and anticoagulant drugs; this is probably due to the fact that clofibrate can affect a variety of hemostatic-related parameters, that is the storage of vitamin K in the liver, or putative receptors for vitamin K (Pond et al., 1975).

Some authors have reported that clofibrate produces a displacement of warfarin from plasma proteins, but concluded that this might not be of clinical relevance (Bjornsson et al., 1979a,b).

Clofibrate displaces other drugs from albumin to variable degrees, e.g, phenylbutazone is displaced by a lesser extent than warfarin. Other mechanisms of the effects of clofibrate on hemostatic parameters involve alterations in the synthesis of some clotting factors and/or changes in the disposition of vitamin K (Brown and Goldstein, 1990; Serlin and Breckenridge, 1983).

Most oral anticoagulants are highly protein-bound drugs showing high constants of dissociation (Kd); therefore they can compete with clofibrate for the binding sites on albumin. The consequence of this effect is the displacement of the anticoagulant drugs with an increase in their unbound or free fraction.

This effect should, but does not always, result in a further decrease in the levels of vitamin K-dependent clotting factors. The prothrombin time is likely to be prolonged in patients on warfarin, if they are also receiving clofibrate. Additionally, an increase in warfarin half-life induced by clofibrate has been observed in dogs; it seems possible that clofibrate may also cause changes in clotting factor levels (Koch-Weser and Sellers, 1971).

Anticoagulants have a narrow therapeutic window; thus, an increase in their unbound, and pharmacologically active, fraction could markedly increase the inhibition of the synthesis of clotting factors. This inhibition produces decreased circulating levels of vitamin K-dependent clotting factors, enhancing the risk of bleeding. The clinical consequences of this interaction can be life-threatening hemorrhages (Solomon and Rosner, 1973). The decrease in clotting factors II and X might also be produced by a more rapid decline in their activities due to a slower coumarin metabolism (O'Reilly et al., 1972; Williams et al., 1976).

When a patient taking tibrates requires treatment with an oral anticoagulant, it is recommended that prothrombin times be monitored frequently in order to adjust the dosage of the oral anticoagulant. It is often necessary to adjust (downward) the dosage of the anticoagulant according to the extent of interaction present, until the prothrombin time has stabilized at the desired level. Neglecting to do so may result in excessive pharmacological effects from the same dose of the oral anticoagulant and the risk of hemorrhage.


2.2.2. Ant id iabe t ics

In addition to the potential benefits ofclofibrate on correcting dyslipidemia secondary to diabetes mellitus, there have been reports of clofibrate administration improving glucose tolerance and decreasing fasting blood-glucose levels as well. It has been hypothesized that clofibrate might reduce insulin resistance, thus improving glucose tolerance and potentiating the therapeutic effects of hypoglycemic drugs, such as the sulfonylureas (Ferrari et al., 1978; Vogelberg et al., 1982) by mechanisms unrelated to their pharmacokinetic interaction.

Another mechanism of interaction between clofibrate and oral hypoglycemic drugs is similar to that of oral anticoagulants; that is, clofibrate competes for protein-binding sites, displacing the hypoglycemic drug from albumin binding sites, and the consequent increase in the unbound fraction of the hypoglycemic drug may result in increased hypoglycemic effects (Odegaard, 1988).

This interaction is especially risky when it occurs with oral hypoglycemic drugs with a long half-life, because the induced hypoglycemia can last several hours or days. This increased frequency of hypoglycemia has also been reported when using intravenous tolbutamide concomitantly with clofibrate (Ferrari et al., 1976).

Biguanides such as metformin may be displaced from protein binding by clofibrate+ resulting in an additive effect on hypoglycemic effects (DeSilva et al., 1979).

Other possible mechanisms of interactions between clofibrate and hypoglycemic drugs have been postulated in experimentally induced diabetes in animals. These interactions are caused by high serum concentrations of clofibrate, resulting in decreased insulin secretion. Clofibrate may also increase lectate utilization when administered with biguanides (Vogelberg et al., 1980; Oliver et al.,

1982). Clofibrate has been shown to decrease insulin release induced by glucose or arginine, but the

mechanisms and/or the clinical consequences of this effect are not fully understood (Odegaard, 1988; Oliver et al., 1982).

It is usually recommended that patients receiving fibrates with other oral hypoglycemic agents be administered a reduced dose of the hypoglycemic drugs, with close monitoring of blood glucose levels, until both drugs have attained a new steady state in plasma concentrations. The published interactions of clofibrate with several hypoglycemic drugs are summarized in Table 1.

2.2.3. In terac t ions with Other Drugs

Rifampin and other drugs capable of inducting hepatic microsomal enzymes have been shown to increase the metabolism ofciofibrate, reducing its serum concentrations and, therefore, decreasing its therapeutic efficacy (Houin and Tillement, 1978; Gut, 1980).

Cholestyramine resin can decrease the rate of absorption of clofibrate. This seems to be of no clinical relevance because there is no documented evidence of lower efficacy of either drug when administered together. Nevertheless. one should be open to the possibility of such interaction between clofibrate and cholestyramine, since levels of the chemically related fibrate derivative -gemfibrozil- have been reported to be lower when administered with cholestyramine (Forland et al., 1990).

Colestipol is also an ion-binding resin, but its binding affinity is somewhat lower than that of cholestyramine, which may explain the fact that colestipol has been shown not to change the serum levels ofchlorophenoxyisobutyric acid--the active metabolite ofclofibrate--or the pharmacokinetic parameters of clofibrate. The authors of this report concluded that these drugs can be administered concomitantly without change in their respective efficacy (De Sante et al., 1979).

Another report, which contradicted these results, analyzed the effects of a combined administration of clofibrate and colestipol at their usual dosages, and found that this drug combination was less effective in lowering total cholesterol and LDL than colestipoi alone at the same dosage (Hunninghake et al., 1981). However, knowing that bile-acid-binding resins tend to increase the levels of serum triglycerides by a direct effect on the lipoprotein regulation mechanism, we believe the reported results could be a consequence of an opposing therapeutic interaction affecting the effectiveness of fibric acids.

Ciofibrate may increase the diuretic effect of furosemide by displacing this drug from its protein-binding sites. Therefore, it is prudent to reduce the dosage of furosemide in patients with

TABLF I. Drug Interactions with CIofibrate

Drug Mechanism of clinical effect Therapeutic actions recommended Reference

Anticoagulants Warfarin Potentiation of anticoagulant

effect Reduction of dosage based on frequent prothrombin time determi- nations Reduce anticoagulant dosage to maintain desired prothrombin level Requires warfarin dose adjustment Reduce the anti-coagulant dosage by one-half

Brown and Goldstein, 1990

Various Increased bleeding

Warfarin Significantly less warfarin needed Various Potentiation of anticoagulant

effects Antidiabetics

Tolbutamide Hypoglycemia; when given together clofibrale may improve glucose tolerance

Rifampin May enhance the metabolism of May be necessary to increase the clofibrate by enzyme induction dose of clofibrate and reduce clofibrate blood levels

Rifampin Induces microsomal enzyme ac- Higher doses of clofibrate may be Odegaard, 1988 tivity and reduces clofibrate blood required levels

Probenecid May cause a reduction in renal and metabolic clearance increasing clofibrate levels and effects

Rosenbcrg, 1984

Eastham. 1973 American Medical Association, 1992

Odegaard, 1988

Houin and Tillement, 1978

Veenendaal et al., 1981

I " O N

~7

¢3

t7 E O < Z ,'n

Drug interactions are mentioned first as a group of drugs and also as individual drugs. A treatment recommendation is included if given by the author reporting or commenting on the interaction.


nephrotic syndrome who have reduced serum albumin levels (Odegaard, 1988). This may be of particular clinical relevance when higher levels of free furosemide may lead to electrolyte imbalance.

Probenecid has been shown to modify the hepatic conjugation of clofibric acid with glucuronide and, as a result, renal clearance of clofibrate. Serum concentrations of clofibrate may rise when these drugs are administered concomitantly (Veenendaal et aL, 1981). In experimental animals, the renal clearance of clofibric acid and clofibric acid glucuronide were reduced by 70-80%, and the area under the curve was increased five-fold when clofibrate was administered simultaneously with probenecid (Meffin et al., 1983).

Probenecid can also displace clofibrate from its protein-binding sites, producing an increase in clofibrate concentration with an increased potential for clofibrate side effects, such as myopathy.

Clomethacin, a drug related to indomethacin, has also been reported to be displaced from albumin by clofibrate and its metabolite, chlorophenoxyisobutyric acid (Zini et al., 1983). Thus, on theoretical grounds, the therapeutic effects, as well as the side effects, of highly protein-bound prostaglandin-inhibiting drugs must be monitored when administered with clofibrate. This is relevant to the fact that arthralgias are often present in dyslipidemic patients and non-steroidal anti-inflammatories are among the most commonly prescribed drugs in such patients (Goupille et al., 1991).

Clofibrate has the largest number of reported interactions with other drugs; these are also the best documented and characterized fibrate interactions. This is likely to be a consequence of clofibrate being the first and most extensively used preparation of its kind.

Gemfibrozil, along with the newest fibrates marketed during the last 10--15 years in countries other than the United States, theoretically may have the same potential interactions with other drugs. Yet, the extent of publications and documentations of such effects is likely to be incomplete. Consequently, it is advisable to be alert to the possibility that any of the fibrate derivatives known to have high protein-binding affinity and to share most pharmacological properties of clofibrate might also interact with other drugs in a similar fashion to clofibrate.

2.3. PHARMACODYNAMIC DRUG INTERACTIONS

2.3.1. Oral Contraceptives

It has long been recognized that the estrogen component in some oral contraceptive preparations may cause an elevation in the blood levels of triglycerides. The progestin components of such preparations may cause a decrease in HDLC, proportionately to their androgenic activity.

The effects of one, or both, of these ingredients of the oral contraceptive drugs may counteract the efficacy of fibrates in correcting dyslipidemia in such patients. If there is an underlying dyslipidemic state, it is advisable to monitor serum lipoprotein levels for 3-6 months in all women who begin using oral contraceptive preparations (Smith and Prior, 1986; Steiner et al., 1991).

The newer oral contraceptive preparations contain much lower amounts of the progestine, as well as the estrogen ingredients, and therefore are less likely to cause these adverse changes in serum lipids. It has been described that women taking clofibrate may greatly increase clofibric acid clearance when started on oral contraceptive agents, and this could result in decrease effectiveness of clofibrate (Miners et al., 1984).

2.3.2. Probucol

This drug, used as a single dyslipidemic intervention, produces a consistent reduction in serum HDLC levels: however, when used in combination with clofibrate, this reduction in serum HDLC levels may be greatly exaggerated. Some authors have mentioned reductions of 60--70% of the initial HDLC levels with this combination. This is a somewhat paradoxical interactive effect since clofibrate can raise the HDLC levels in blood and can be expected to counteract the lowering of serum HDLC levels consistently found after probucol administration. The actual mechanism of this interesting and perplexing interactive effect is poorly understood (Yokoyama et al., 1988).


3. GEMFIBROZIL

3.1. GENERAL PHARMACOLOGY AND THERAPEUTIC EFFECTS

The pharmacological characteristics of this drug that are important in relation to its potential for drug interactions are: (a) its high protein binding; (b) its half-life of 2-8 hr; (c) the steady state reached after 3-4 days of therapy; (d) its extracellular distribution; and (e) its extensive metabolism, with a small fraction of the parent drug eliminated by the kidney (Knauf et al., 1990).

Gemfibrozil produces reductions in triglyceride levels to an equal extent and by similar mechanisms to those of clofibrate. It decreases VLDL cholesterol production in the liver and increases lipoprotein lipase activity, thus decreasing serum triglycerides. It has consistent effects on LDLC levels. In certain hypertriglyceridemic patients, the serum levels of the LDLC fraction may increase. Gemfribrozil has no effect on plasma fibrinogen; it increases the lithogenic index of bile (Todd and Ward, 1988).

Gemfibrozil is the most commonly used fibrate derivative in the United States; it is mostly prescribed in type lib and IV hyperlipidemias and, like clofibrate, has the greatest efficacy in the more rare type III disease. It is also utilized in diabetic patients with elevated total cholesterol and triglycerides and/or low HDLC levels. The number of patients treated for lipid disorders secondary to diabetes mellitus, nephrosis or other diseases, is much smaller than the number treated for primary dyslipidemias.

Gemfibrozil reduces total cholesterol and triglycerides levels, has variable effects on LDLC levels and increases HDLC levels. It has proven to be safe and to reduce the incidence of cardiac events in a large, placebo-controlled, long-term clinical trial, so it is likely that there could be expansion in its utilization and clinical indications (Frick et al., 1987).

3.2. PHARMACOKINETIC DRUG INTERACTIONS

Interactions involving the displacement of drug-protein binding by gemfibrozil when used concomitantly with salicylic acid, acenocumarol, furosemide, valproic acid, tolbutamide, warfarin and sulfamethoxazol have been reported as either absent or minimal; small degrees of interaction for some of these drugs have been described in detail (Hamberger et al., 1986; Todd and Ward 1988) (see Table 2).

3.2. I. Anticoagulants

Gemfibrozil can interact with oral anticoagulants by the same mechanisms and to the same extent as described above for clofibrate. The displacement of oral anticoagulants from their plasma-protein binding could lead to increased levels of free (unbound) drug and to potential bleeding complications. Therefore, the dose of coumadin-type drugs should be adjusted and the prothrombin time carefully monitored when these drugs are coadministered (Todd and Ward, 1988).

Ahmad (1990) reported that the hepatic parahydroxylation of warfarin can be inhibited by gemfibrozil, thus producing higher warfarin levels with a further decrease in the synthesis of clotting factors, leading to risk of bleeding episodes.

3.2.2. Antidiabetics

There is a report of an interaction between gemfibrozil and glyburide, resulting in clinical hypoglycemia (Ahmad, [991). The author describes drug challenge, dechallenge and rechallenge with the expression of the same hypoglycemic symptoms on all occasions and hypothesizes that gemfibrozil displaces glyburide from its protein-binding sites.

3.2.3. Interactions with Other Drugs

Colestipol can reduce the absorption of gemfibrozil when both drugs are coadministered, producing lower gemfibrozil serum concentrations, with a decrease in the area under the curve. The authors of this study concluded that there is a reduction in the bioavailability of gemfribrozil due

TABLE 2. Drug Interactions with Gemfibrozil

Drug Mechanism of clinical effect Therapeutic actions recommended Reference

Anticoagulants

Warfarin

Antidiabetics

Glyburide

Lovastatin

Lovastatin

Lovastatin

Colestipol

Potentiation by displacement from albumin Decrease in liver metabolism with increase in serum levels and potential for bleeding Gemfibrozil per se might have a hyperglycemic effect Displaces glyburide from its protein binding sites with subsequent hypoglycemia Myositis, rhabdomyolysis and in some cases, renal failure

Myositis with increased serum CPK levels Severe myopathy or rhabdomyolysis and serum CPK levels above 10,000 U/L Reduction of gemfibrozil bioavailability when administered concomitantly

Awareness of the potential risk of this interaction

Adjust the dosage of oral hypoglycemics or insulin Monitor glucose levels closely and adjust glyburide dosage

Avoid combined use, when possible, or, if needed, lower the doses of each and monitor side effects closely

Discourage the use of this combination

Separate the administration of the drugs by at least 2 hr


Ahmad, 1990


Ahmad, 1991

Zimetbaum et al., 1991

Margarian et al., 1991

Pierce et al., 1990

Forland et al., 1990

tj~

5"

~_.

Drug interactions are mentioned first as a group of drugs and also as individual drugs. A treatment recommendation is included if given by the author reporting or commenting on the interaction.

",4


to its binding to colestipol in the gut, but that this interaction does not affect the therapeutic response to colestipol (Forland et al., 1990).

3.2.4. On the Issue o f M y o p a t h y Potent ia t ion be tween Gernfibrozil and Lovas ta t in

There are several primary and secondary dyslipidemias that, in order to obtain adequate control and/or correction of serum lipid levels, require treatment either with the highest dose of single hypolipidemic drugs or with drug combinations.

Patients requiring combined therapy may receive gemfibrozil with hydroxymethylglutaryl coenzyme A inhibitors (statins). Statins can cause myopathy in 0.1-0.2% of patients, but their combination with gemfibrozil has been reported to produce myopathy in 0.5 5.0% of patients. The spectrum of this interaction can range from mild muscle tenderness and myositis with minimal serum creatinine phosphokinase (CPK) elevation to serve rhabdomyolysis, myo- globinuria and, in some cases, renal failure (Magarian et al., 1991; Zimetbaum et al., 1991; Pierce et al., 1990; Smith et al., 1991).

Some authors have speculated that the myopathy produced by this drug combination might be caused by a reduction in the endogenous synthesis of muscle cholesterol by these drugs. Others have reported that isomers of clofibrate and other chemically related compounds have produced a change of chloride conductance in muscle chloride channels in experimental animals (Conte- Camerino et al., 1988; Feller et al., 1987: Pierce et al., 1990).

Electron microscopy of muscle biopsies of patients with clinical myopathy on the so-called clofibrate-induced muscular syndrome (myalgia, weakness, malaise and elevated CPK) showed atrophy of muscle fibers with irregularities and disruption of the Z-band material and dilated vacuoles (Rimon et al., 1984). It is assumed that gemfibrozil effects will be of the same nature.

This is no complete understanding of the mechanisms involved in the reports of myotoxic interaction between gemfibrozil and lovastatin. Some insight can be gained from the interaction between Iovastatin and cyclosporine, where it has been documented that cyclosporine administration results in increased serum levels of Iovastatin. It has been assumed that the cyclosporine- induced elevations in Iovastatin serum levels result in greater risks of myopathy induced by lovastatin (Smith et al., 1991).

It, therefore, is advisable to be alert to the occurrence of muscle pain and to monitor serum CPK values whenever a patient is receiving fibrates and statin concomitantly in order to be able to detect this interaction as early as possible.

In patients receiving fibrates with cyclosporine, the latter drug may alter lipoprotein regulation, increasing LDLC and/or other lipoproteins, making these patients more resistant to the hypolipidemic efficacy of the drugs and in some cases, creating the need for multiple drug combination therapy (Schorn et al.. 1991: Kasiske et al., 1991; Raine et al., 1988; Ballantyne et al., 1989; Webb et al., 1992. 1993).

Many patients with renal failure have secondary dyslipidemia and thus, may require lipid-acting treatment. In those patients, the serum half-life of gemfibrozil can be prolonged because of decreased excretion, secondary to renal insufficiency.

It is advisable to reduce the dose of fibrates by half whenever the patient has a diminished creatinine clearance in the range of 50 20 mL/min. The reduction should be even greater when the creatinine clearance is below this value.

3.3. PHARMA('ODYNAMIC DRUG INTERACTIONS

When probucol is used alone, serum HDLC levels may fall in many patients, but when it is used concomitantly with gemfibrozil, the HDLC values may be further reduced. This is a paradoxical effect similar to that described in Section 2.2.3, when probucol is administered with clofibrate or bezafibrate (Klosiewicz-Latoszek and Szostak, 1991: Yokoyama et al., 1988).


4. FENOFIBRATE

This drug, chemically related to clofibrate, is not marketed in the United States but has been available in other countries since 1973. As the other drugs in this group, it is effective in lowering serum cholesterol and triglyceride levels, also producing increases in serum HDLC levels. Fenofibrate has a greater serum LDLC reducing effect than other fibrates (Hunninghake and Peters, 1987).

Fenofibrate is a prodrug that is hydrolyzed after absorption and converted into fenofibric acid, its active form. It has a long half-life (20-27 hr), producing steady-state concentrations after 5 days of continuous dosing. It is 99% bound to plasma proteins and has a large volume of distribution (Balfour et al. , 1990).

In the United States multicenter study, in 92 type lla patients, fenofibrade reduced total serum cholesterol levels by 18%, LDLC levels by 20% and VLDL cholesterol levels by 38%. Similar results were seen in comparison to the placebo group in 24 type lib patients (Brown et al., 1986). Other trials have reported similar results (Canzler and Bojanouski, 1980; Malmendier and Delcroix, 1985). When fenofibrate was used in combination with colestipol, there was a 31% decrease in the LDLC (Baggio et al., 1986, Weisweiler et al., 1986). In a review of fenofibrate safety, the National Heart, Lung and Blood Institute (Bethesda, MD) concluded that it is a safe and well-tolerated drug (Roberts, 1989).

Given the possibility that the drug may be used simultaneously with other lipid-lowering drugs, some authors have studied its pharmacokinetic parameters, measuring the plasma and urinary concentrations when it was administered alone and when administered concomitantly with colestipol. They did not find any reduction in serum or urinary levels of fenofibrate, and concluded that there arc no clinically significant drug interactions between these drugs. When serum fenofibrate levels were measured, the higher the serum levels the greater the lowering of serum triglycerides (Sirtori et al. , 1985; Harveng and Desager, 1980).

Studies in diabetic patients showed fenofibrate to have a tendency to lower blood glucose values, without a need to adjust the dosage of the antidiabetic drug (Blane, 1987; Roberts, 1989; Brown et al. , 1986).

A case of an interaction with an oral anticoagulant was described where a reduction of the dose of fenofibrate by one-third allowed a return to the previous prothrombin-time values (Roberts, 1989).

An increased clearance of uric acid with lower serum uric acid levels has been described, but the mechanism was unclear and the significance of this for drug interactions was not fully understood (Harvengt et al. , 1980, Desager et al. , 1980).

5. CIPROFIBRATE

This is another fibric acid derivative that is used less than the fibrates discussed previously. Therefore, it is important to note that many of its potential interactions may not yet have been reported. This drug is currently recommended to be administered once a day, due to its long half-life (24-42 hr); similar to the other drugs, it has high affinity for serum-protein binding (99%). It has been reported to be more efficacious than fenofibrate in increasing HDLC levels, with the advantage of a single daily dosage (Olsson and Oro, 1982; Rouffy et al., 1985).

6. BEZAFIBRATE

This drug has been available in some countries since 1978 and has a similar efficacy and safety to other drugs of the group. Some authors have reported that it is more effective than fenofibrate and when compared with gemfibrizol it produces a more pronounced effect on LDLC and HDLC (Tesone et al. , 1985; Weisweiler, 1988). It has a shorter half-life than the other tibrates but is 95% protein-bound. To our knowledge, there are no drug interactions reported to date (Blane, 1987).


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Drug interactions with fibric acids

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