EFFECTS OF ALCOHOL-CONSUMPTION ON PHARMACOKINETICS, EFFICACY, AND SAFETY OF FLUVASTATIN

Alcohol consumption is known to have beneficial effects on cardiac mor tality, probably by increasing high density lipoprotein cholesterol (H DL-C). Alcohol also increases triglycerides and, in some studies, tota l cholesterol and low density lipoprotein cholesterol (LDL-C). Nothing is known, however, of the effects of alcohol on the pharmacokinetics and efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduct ase inhibitors. Consequently, 2 studies have been carried out to deter mine the effects of alcohol consumption on the pharmacokinetics and ef ficacy of the HMG-CoA reductase inhibitor fluvastatin. Firstly, the ef fects of acute alcohol consumption on a single, oral 40 mg dose of flu vastatin were examined in a reference-controlled, randomized, crossove r study in 10 healthy volunteers. Measurements were made after ingesti on of 70 g of ethanol diluted to 20% with lemonade and, following a 7- day period, after ingestion of lemonade alone (reference). The half-li fe (t(l/2)) of a single dose of fluvastatin was significantly reduced by acute alcohol consumption compared with reference, whereas the area under the time-concentration curve (AUC), peak concentration (C-max), and time to peak concentration (t(max)) did not differ from the refer ence group. The lipid profile, measured 8 hr after administration, did not differ significantly from baseline in the reference group, apart from a slight reduction in apolipoprotein (apo)-Al. Triglyceride level s increased with alcohol, probably due to impaired fatty acid oxidatio n. Surprisingly, total cholesterol and LDL-C fell significantly, possi bly due to altered pharmacokinetics, as reflected by the lower t(1/2). To assess the long-term clinical implications of these findings, a 6- week study into the effects of alcohol consumption on fluvastatin phar macokinetics and lipid-lowering capacity was conducted in 26 patients with primary hypercholesterolemia (LDL-C 4.2 mmol/liter after dietary baseline period). Patients were randomized to 6-week treatment with 40 mg/day of fluvastatin, combined with either 20 g of alcohol diluted t o 20% with lemonade, or with lemonade alone (reference). After a 6-wee k washout period, the 2 groups crossed over for a second 6-week treatm ent period. Measurements were made at the end of each treatment period . In the 20 patients who completed the study, no serious adverse event s occurred. Alcohol did have some effect on fluvastatin pharmacokineti c parameters; a tendency to lengthen t(1/2) and to increase AUC and t( max) compared with reference, without a difference in C-max between re ference and alcohol. However, these pharmacokinetic effects did not co rrelate with differences in lipid parameters. Neither reference nor al cohol showed significant changes in HDL-C or triglyceride levels, but significant decreases in total cholesterol, LDL-C, and apo B were obse rved; these decreases did not differ significantly between reference a nd alcohol. In conclusion, alcohol consumption has no effect on the ef ficacy and safety of fluvastatin treatment in patients with primary hy percholesterolemia.