ABSTRACT:The active forms of all marketed hydroxymethylglutaryl (HMG)-CoA reductase inhibitors share a common dihydroxy heptanoic or heptenoic acid side chain. In this study, we present evidence for the formation of acyl glucuronide conjugates of the hydroxy acid forms of simvastatin (SVA), atorvastatin (AVA), and cerivastatin (CVA) in rat, dog, and human liver preparations in vitro and for the excretion of the acyl glucuronide of SVA in dog bile and urine. Upon incubation of each statin (SVA, CVA or AVA) with liver microsomal preparations supplemented with UDP-glucuronic acid, two major products were detected. Based on analysis by high-pressure liquid chromatography, UV spectroscopy, and/or liquid chromatography (LC)-mass spectrometry analysis, these metabolites were identified as a glucuronide conjugate of the hydroxy acid form of the statin and the corresponding ␦-lactone.

Aims Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion‐transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. Methods The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. Results Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration–time curve were 5.7‐ and 7.6‐fold for pitavastatin and 4.4‐ and 3.3‐fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. Conclusions The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.

ABSTRACT:This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of ␤-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a ␤-oxidation product (IC 50 ϳ50 and 15 M, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC 50 ϳ50-60 M) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC 50 ϳ30 to 60 M) the lactonization of all three statins. As was observed previously with other statin hydroxy acids, RVA underwent significant glucuronidation to form an acyl glucuronide conjugate and lactonization to form RVA lactone in human liver microsomes and by UGT 1A1 and 1A3. While GFZ is not an inhibitor of CYP3A4, it is a competitive inhibitor (K i ‫؍‬ 87 M) of CYP2C8, a major catalyzing enzyme for CVA oxidation. These results suggest that 1) the pharmacokinetic interaction observed between GFZ and statins was not likely mediated by the inhibitory effect of GFZ on the ␤-oxidation, but rather by its effect primarily on the glucuronidation and non-CYP3A-mediated oxidation of statin hydroxy acids, and 2) there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans.Fibrates, lipid-regulating agents, and hydroxymethylglutaryl-coenzyme A reductase inhibitors or so called "statins", cholesterol lowering agents, are frequently prescribed together to treat patients with mixed hyperlipidemia (Shek and Ferrill, 2001). There have been reports of increased risk of myopathy, including rhabdomyolysis with this coadministration (Murdock et al., 1999). Despite being generally accepted as a class effect for all fibrate-statin combinations, this increased risk has been observed at varied incidences with different fibrates and statins. More documented cases for myopathy have been reported with gemfibrozil (GFZ 1 )-statin combined therapy than with other fibrate-statin combinations (Shek and Ferrill, 2001). Recently, cerivastatin (CVA) was withdrawn from the market due to disproportionate numbers of fatal rhabdomyolysis cases (compared with other marketed statins), many of which occurred in patients receiving concomitant GFZ (Farmer, 2001).Although it has generally been accepted that the increased risk of myopathy is due primarily to a pharmacodynamic drug-drug interaction, recent studies have suggested that the increased risk might also have a pharmacokinetic origin. In recent clinical studies, increases in the exposure mainly to statin hydroxy acids, but minimally to the lactone form of statins, were observed following coadministration of GFZ and statins (Backman et al., 2000;Kyrklund et al., 2001). Subsequently, ...

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