Effects of gemfibrozil and clofibric acid on the uptake of taurocholate by isolated rat hepatocytes

Sabordo, Lucia; Sallustio, Benedetta C.

doi:10.1016/s0006-2952(97)00146-9

Cited by 3 publications

(3 citation statements)

References 15 publications

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“…at ASPET Journals on May 12, 2018 dmd.aspetjournals.org good substrate of organic anion transporter polypeptide (Brown et al, 2001), and GFZ has been shown to be an inhibitor, although not potent, of taurocholate uptake in rat hepatocytes (Sabordo and Sallustio, 1997). In contrast, decreased uptake of SVA, AVA, and CVA into hepatocytes by GFZ is not likely a major cause for the diminished statin lactonization observed since differential effects of GFZ were observed on the oxidation versus the lactonization of the three statins in this system.…”

Section: Prueksaritanont Et Almentioning

confidence: 99%

Effects of Fibrates on Metabolism of Statins in Human Hepatocytes

Prueksaritanont¹,

Tang²,

Qiu³

et al. 2002

Drug Metab Dispos

307

187

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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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Section: Prueksaritanont Et Almentioning

confidence: 99%

Effects of Fibrates on Metabolism of Statins in Human Hepatocytes

Prueksaritanont¹,

Tang²,

Qiu³

et al. 2002

Drug Metab Dispos

307

187

View full text Add to dashboard Cite

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“…Among the fibrates, gemfibrozil is associated with the highest risk of myotoxicity, in monotherapy or combination with statins (Holoshitz et al 2008; Liu et al 2009). In the clinic, gemfibrozil also increases risk of cholestatic jaundice and cholelithiasis (Sabordo and Sallustio 1997; Roglans et al 2004). It is contraindicated in patients with a history of gallbladder disease.…”

Section: Introductionmentioning

confidence: 99%

“…Extensive efforts have been taken to understand the role of PPARα in BA homeostasis, but the results are contradictory. In rat hepatocytes, gemfibrozil and clofibric acid were found to inhibit taurocholate uptake, but they do not appear to directly alter the hepatic uptake of taurocholate because the Ki values were much higher than their clinical concentrations (Sabordo and Sallustio 1997). Sterol 12α-hydroxylase, a branch-point enzyme in the bile acid biosynthetic pathway, was reported to be upregulated in wild-type mice after Wy-14,643 treatment, as well as fasting conditions, which was diminished in Ppara-null mice (Hunt et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity

et al. 2014

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Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

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