Gemfibrozil greatly increases plasma concentrations of cerivastatin.
BACKGROUND
Concomitant use of gemfibrozil with statins, particularly with cerivastatin, increases the risk of rhabdomyolysis, but the mechanism of this potentially fatal drug interaction remains unclear. Our aim was to study the effect of gemfibrozil on cerivastatin pharmacokinetics.


METHODS
In a randomized, double-blind crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 3 days. On day 3, each subject ingested a single 0.3-mg dose of cerivastatin. Plasma concentrations of cerivastatin, its metabolites, and gemfibrozil were measured up to 24 hours.


RESULTS
During gemfibrozil treatment, the area under the plasma concentration-time curve [AUC(0-infinity)] of parent cerivastatin was on average 559% (range, 138% to 995%; P =.0002) and the peak concentration in plasma was 307% (138% to 809%; P =.0019) of the corresponding values in the placebo phase. Gemfibrozil increased the AUC(0-infinity) of cerivastatin lactone, on average, to 440% (94% to 594%; P =.0024) and that of metabolite M-1 to 435% (216% to 802%; P =.0002) of the control (placebo) values, whereas the AUC(0-24) of metabolite M-23 was decreased to 22% (11% to 74%; P =.0017).


CONCLUSIONS
Gemfibrozil greatly increases plasma concentrations of cerivastatin, cerivastatin lactone, and metabolite M-1, whereas the level of metabolite M-23 is markedly reduced by gemfibrozil. Gemfibrozil therefore inhibits the formation of M-23, which is thought to be dependent on CYP2C8. The increased exposure to cerivastatin in the presence of gemfibrozil may explain the high incidence of myopathy observed with this combination, although the role of pharmacodynamic interactions between these 2 agents cannot be excluded.
Backman
Janne T
JT
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Kyrklund
Carl
C
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D012206:Rhabdomyolysis / Q000139:chemically induced
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D011725:Pyridines; C086276:cerivastatin; D015248:Gemfibrozil