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 tookgemfibrozil (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.
RCT Entities:
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.
Authors: Manthena V S Varma; Yurong Lai; Bo Feng; John Litchfield; Theunis C Goosen; Arthur Bergman Journal: Pharm Res Date: 2012-05-26 Impact factor: 4.200
Authors: Mikko Niemi; Aleksi Tornio; Marja K Pasanen; Hanna Fredrikson; Pertti J Neuvonen; Janne T Backman Journal: Eur J Clin Pharmacol Date: 2006-04-27 Impact factor: 2.953