Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance.
BACKGROUND
Gemfibrozil increases the plasma concentrations of active acid forms of cerivastatin, lovastatin, and simvastatin. Pravastatin pharmacokinetics differs from those of these 3 statins, which are extensively metabolized. Our aim was to study the effects of gemfibrozil on the pharmacokinetics of pravastatin.


METHODS
A randomized, placebo-controlled, 2-phase crossover study was carried out. Ten healthy volunteers took gemfibrozil (1200 mg/d) or placebo for 3 days. On day 3, each subject ingested a single 40-mg dose of pravastatin. The concentrations of pravastatin and gemfibrozil in plasma and the cumulative excretion of pravastatin into urine were measured up to 24 hours.


RESULTS
During the gemfibrozil phase, the mean total area under the plasma concentration-time curve (AUC) of pravastatin from 0 hours to infinity was 202% (range, 40%-412%) of the corresponding value during the placebo phase (P <.05), but there was no difference in the half-life between the phases. The renal clearance of pravastatin was reduced from 25 L/h to 14 L/h by gemfibrozil (P <.0001), but the cumulative excretion of pravastatin into urine did not change significantly. The increase in the AUC of pravastatin from 0 to 24 hours correlated significantly with the decrease in the renal clearance of pravastatin (r = 0.72, P =.02). However, the change in renal clearance was only a minor contributor to the increase in pravastatin AUC.


CONCLUSIONS
Gemfibrozil increases plasma concentrations of pravastatin. This is partly but not solely the result of the reduced renal clearance of pravastatin. The increase in pravastatin AUC from 0 hours to infinity by gemfibrozil may represent an interference with a transport protein.
Kyrklund
Carl
C
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Backman
Janne T
JT
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil / Q000009:adverse effects* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism*; D008297:Male; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D017035:Pravastatin; D015248:Gemfibrozil