Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers

Abstract

The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum-proximal jejunum in 8 healthy volunteers. Bile and plasma samples were collected every 20 minutes for 200 minutes, with additional plasma samples being drawn for up to 48 hours. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC(plasma,200min)) by 1.56-fold (95% confidence interval, 1.14-2.15). The interaction was less pronounced in this single-dose study than in a previous report when gemfibrozil was administered repeatedly; nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

“…Factors affecting this pathway can have a significant impact on the hepatic concentration, clearance, and toxicity of drugs or their metabolites (Stieger et al, 2000;Kostrubsky et al, 2001;Endres et al, 2006Endres et al, , 2009Feng et al, 2009;Ohtsuki et al, 2012). In humans, the measurement of the in vivo biliary clearance of drugs is difficult unless the intestine is catheterized (Bergman et al, 2010). Thus, in vitro methods such as sandwich-cultured human hepatocytes are often used to estimate the contribution of biliary clearance to the overall clearance of drugs.…”

Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association

“…Consistent with other statins reviewed above, gemfibrozil increased plasma concentrations of rosuvastatin by ≈1.56-to 1.88-fold. 59,60 Gemfibrozil had only a modest effect when administered with pitavastatin in 24 subjects with an increase of 45% in the AUC. 61 Metabolism is only a minor pathway for pitavastatin via CYP2C9, which is unaffected by gemfibrozil.…”

In vitro Anti-Cancer Activity of Rosuvastatin and Ketorolac Nanoformulations against DDX3

“…[42][43][44] RST belongs to the class III compound as per the biopharmaceutical classification system (BCS), which is having low permeability and high solubility. 45 Apart from said activities of RST, presently statins have been evaluating for anticancer properties. Self-Nanoemulsifying Drug Delivery System of RST has shown antitumor action in Caco-2 cells 46 , Cytotoxic effects on HepG2 cells 47 , inhibits arginase enzyme which is responsible for breast cancer 48 , decreased risk of cancer-related mortality, with a reduction of up to 15%.…”