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Effects of Alcohol and Fluvastatin on Lipid Metabolism and Hepatic Function
- Jan W. Smit, MD;
- Herman J. Wijnne, PhD;
- Fred Schobben, PhD;
- Ad Sitsen, MD, PhD;
- Tjerk W. De Bruin, MD, PhD; and
- D. Willem Erkelens, MD, PhD
- From University Hospital, Utrecht, the Netherlands. Requests for Reprints: Jan W. Smit, MD, Department of Internal Medicine, Room F.02.126, University Hospital, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Abstract
Objective: To determine the effects of fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, combined with moderate alcohol consumption on lipid profiles and hepatic function in patients with primary hypercholesterolemia.
Design: Randomized, placebo-controlled, crossover study.
Setting: Lipid clinic of a university hospital.
Patients: 31 patients with primary hypercholesterolemia (low-density lipoprotein cholesterol levels ≥ 4.2 mmol/L) who had previously received a lipid-lowering diet.
Interventions: After a dietary baseline period, 26 patients were randomly assigned to receive 6 weeks of treatment with either 1) fluvastatin, 40 mg/d, added to 20 g of ethanol and diluted to 20% with orange juice or 2) fluvastatin added to orange juice alone. After a 6-week washout period, the two groups crossed over.
Main Outcome Measures: Plasma fluvastatin levels, lipid levels, and clinical variables were determined at the end of each treatment period.
Results: Six patients left the study prematurely. The remaining patients (15 men, 5 women; mean age ±SD, 49.1 ±14.5 years; mean body mass index ±SD 24.5 ±2.2 kg/m2) completed the study. Fluvastatin, alone and combined with alcohol, resulted in similar decreases in levels of total cholesterol (22% and 23%, respectively; P < 0.001 when compared with baseline), low-density lipoprotein cholesterol (28% and 29%, respectively; P < 0.001 compared with baseline), and apolipoprotein B (17% and 20%, respectively; P < 0.001 compared with baseline). High-density lipoprotein cholesterol and triglyceride levels were not changed. Fluvastatin with alcohol resulted in a significantly greater area under the plasma concentration curve (23.4 ±4.7 compared with 18.2 ±3.2 × 103 ng x min/mL) and in a greater time to maximum concentration (187.5 ±16.6 min compared with 130.9 ±7.0 min) than fluvastatin alone. Terminal half-life tended to increase. No important adverse clinical effects were observed.
Conclusion: Six weeks of daily, moderate alcohol consumption influenced the metabolism of fluvastatin but did not interfere with its lipid-lowering efficacy and had no adverse effects.
Inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are now widely used for the treatment of hypercholesterolemia. They cause a decrease in intracellular cholesterol concentrations, which leads to a compensatory synthesis of receptors for low-density lipoprotein (LDL) cholesterol [1, 2]. Although these drugs are considered relatively safe, incidental increases in serum aminotransferases and creatine kinase (seldom accompanied by myopathy) have been reported [3, 4]. Treatment with HMG-CoA reductase inhibitors is generally lifelong; therefore, the influence of lifestyle on efficacy and adverse events should be considered. Because alcohol consumption is widespread in most Western countries, patients receiving treatment with HMG-CoA reductase inhibitors probably need advice about alcohol consumption; however, it is not clear what advice they should receive. Moderate alcohol consumption has been reported to have beneficial effects on patients with cardiovascular disease [5, 6]; these effects have been attributed in part to increased levels of high-density lipoprotein (HDL) cholesterol [7]. However, the hepatic metabolism of many drugs is affected by alcohol [8]. Because HMG-CoA reductase inhibitors are extracted from the circulation and metabolized by the liver (their main site of action), interference with this mechanism could have implications for efficacy and could lead to increased systemic levels of these drugs and to potentially adverse reactions. For example, muscle toxicity has been associated with increased systemic levels of HMG-CoA reductase inhibitors [2, 9].
To determine the effects of HMG-CoA reductase inhibitors combined with moderate alcohol consumption [10] on lipid profiles and hepatic function, we did a randomized, crossover trial in patients with hypercholesterolemia who were treated for 6 weeks with fluvastatin, either alone or combined with ethanol (20 g/d). Fluvastatin is a synthetic HMG-CoA reductase inhibitor that lowers levels of total cholesterol and LDL cholesterol by 25% and 30%, respectively, when used at doses of 40 mg/d [11].
Methods
Patients
Thirty-one patients with primary hypercholesterolemia (LDL cholesterol levels ≥ 4.6 mmol/L and triglyceride levels < 4.6 mmol/L) were recruited from the lipid clinic of University Hospital Utrecht. Exclusion criteria were liver and kidney disease, malignancies, and unstable cardiac disease. No concomitant therapy with drugs affecting lipid metabolism was allowed. The maximal habitual alcohol consumption allowed was 10 units/wk (one unit contains 10 g of ethanol [one glass of beer or wine]).
Study Protocol
The protocol was approved by the hospital ethics committee, and informed consent was obtained from all participants. The design was a placebo-controlled, crossover study. All participants received a standard lipid-lowering diet before drug treatment. At the end of an 8-week dietary baseline period, patients with LDL cholesterol levels of 4.2 mmol/L or more and triglyceride levels of less than 4.6 mmol/L were randomly assigned to receive treatment. For 6 weeks, patients received either 1) fluvastatin, 40 mg/d [taken at bedtime], added to 20 g of ethanol and diluted to 20% with orange juice or 2) fluvastatin, 40 mg/d, added to orange juice alone (control). Alcohol or orange juice and the fluvastatin were ingested more than 2 hours after the evening meal and within 1 hour of ingestion of the fluvastatin. After a 6-week washout period, the two groups crossed over and followed the same protocol.
During an overnight stay at the end of each treatment period, a blood sample was taken before ingestion of fluvastatin (time = 0 [11 p.m.]); blood samples were also taken 30, 45, 60, 90, 120, 180, 300, and 540 minutes after ingestion of the fluvastatin for determination of plasma levels of fluvastatin. Fasting lipid levels were determined before and at the end of the two treatment periods. Dietary adherence was checked by a 3-day food log during the baseline and the washout periods. During the study, a maximal additional alcohol consumption of two units/wk was allowed. Clinical laboratory variables, pulse, weight, and blood pressure were assessed at every visit.
Measurements
Assessment of plasma lipid levels and clinical laboratory variables (creatinine, sodium, potassium, bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, crea-tine kinase) a hematologic profile, and urinary analysis were done by standard laboratory methods. Low-density lipoprotein cholesterol levels were calculated using the Friedewald formula [12].
Fluvastatin levels were determined by high-performance liquid chromatography as described previously [13]. Fluvastatin pharmacokinetic variables were maximum concentration in plasma (Cmax), time to maximum plasma concentration (Tmax), area under the concentration curve (using the trapezoidal method), and terminal half-life (estimated by linear regression analysis of the terminal log-linear phase of the concentration-time curve) [14].
Statistical Methods
Results were analyzed for carryover effects [15]. In the absence of such effects, results of both randomization groups were combined and analyzed with a two-sided, paired Student t-test. When a carryover effect was suspected, data from the first treatment period were analyzed using an unpaired t-test. Data are expressed as means ±SE unless stated otherwise. A P value of less than 0.05 was considered statistically significant.
Results
Five patients were not randomly assigned because their lipid values returned to normal during the baseline period. Six patients withdrew from the study in the first treatment period: three because they felt inebriated by the alcohol, one patient because tendon xanthomata developed and the amount of decrease in the levels of cholesterol was not satisfactory, and two patients for reasons unrelated to the study.
The remaining 20 patients (male/female ratio, 15/5; age ±SD, 49.1 ±14.5 years; and body mass index ±SD, 24.5 ±2.2 kg/m2) completed the study; 12 patients received fluvastatin with ethanol, and 8 patients received fluvastatin alone. At the end of each treatment period, no adverse events were observed (except for increased levels of γ-glutamyltransferase in two patients and of creatine kinase in one patient; none of these increases caused symptoms).
Although no significant carryover effect was detected for any variable [15], regression coefficients for half-life differed considerably between the study groups (0.80 and 0.03, respectively). Therefore, for half-life, only the first treatment period was analyzed.
Effect on Plasma Lipid Levels
Baseline lipid levels did not differ between treatment periods (Table 1). Six weeks of therapy with fluvastatin (40 mg/d) alone or combined with alcohol resulted in nearly identical decreases in levels of total cholesterol (22% and 23%, respectively), LDL cholesterol (28% and 29%, respectively), and apolipoprotein B (17% and 20%, respectively). Levels of HDL cholesterol and triglyceride did not change significantly in either treatment period.
Fluvastatin Pharmacokinetic Variables
The area under the plasma concentration curve for fluvastatin with alcohol (23.4 ±4.7 × 103 ng x min/mL) was larger than for fluvastatin alone (18.2 ±3.2 × 103 ng x min/mL; P = 0.030) (Table 2). The time to maximum plasma concentrations of fluvastatin was greater for fluvastatin with alcohol (187.5 ±16.6 minutes) than for fluvastatin alone (130.9 ±17.0 minutes; P = 0.022); Cmax did not differ (Table 2). Terminal half-life could not be calculated in five participants because no terminal log-linear phase could be described within the sampling period for these participants. In the remaining 15 patients, a carryover effect could not be excluded. In the first treatment period, the half-life was longer for fluvastatin with alcohol (103.9 ±7.1 minutes) than for fluvastatin alone (81.7 ±4.8 minutes; P = 0.044).
Discussion
We assessed the effects of the HMG-CoA reductase inhibitor fluvastatin, combined with alcohol, on lipid profiles and hepatic function. Six weeks of treatment with fluvastatin, 40 mg/d, resulted in significant decreases in levels of total cholesterol and LDL cholesterol that were uninfluenced by daily consumption of 20 g of ethanol. Although alcohol has been reported to increase HDL cholesterol and triglyceride levels [7, 16], addition of alcohol to fluvastatin in our study did not affect levels of these lipids.
Pharmacokinetic variables, including Cmax and Tmax, were increased for fluvastatin and alcohol compared with fluvastatin alone. Because half-life could be analyzed in only 15 patients and a carryover effect could not be excluded, we can only conclude that concomitant use of alcohol might prolong the terminal half-life of fluvastatin.
Oxidation of ethanol by hepatic alcohol dehydrogenase reduces the oxidizing capacity of the liver, which may impair intrahepatic drug metabolism [8, 17]. Prolonged alcohol consumption can induce an additional ethanol oxidizing route (for example, the microsomal ethanol oxidizing system, which is part of the cytochrome P-450 system [18]). Because many xenobiotics (including HMG-CoA reductase inhibitors) are metabolized by cytochrome P-450 [19], this is another mechanism by which ethanol interferes with drug metabolism. This may explain the higher area under the plasma fluvastatin concentration curve and the prolonged terminal half-life during alcohol consumption. The longer Tmax of fluvastatin in patients consuming alcohol, which reflects prolonged absorption, may be explained by delayed gastric emptying during alcohol consumption [20]. In normal situations, only a small proportion of an oral dose of an HMG-CoA reductase inhibitor reaches the systemic circulation. Although with alcohol consumption, this proportion may be increased (reflected by the increased area under the curve), it is still a negligible part of the total dose. This presumably explains why alcohol did not affect the lipid-lowering efficacy of fluvastatin and may also explain the absence of systemic adverse effects, which are generally attributed to high systemic drug levels [2, 9].
We found that 6 weeks of moderate alcohol consumption did not affect the lipid-lowering efficacy of fluvastatin, although some effects on drug metabolism were observed. Although no adverse effects were observed during 6 weeks of treatment, our findings should probably not be extrapolated to long-term treatment with fluvastatin in patients who consume large amounts of alcohol.
- Copyright ©2004 by the American College of Physicians
