Atorvastatin Glucuronidation Is Minimally and Nonselectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate, and Fenofibric Acid

Goosen, Theunis C.; Bauman, Jonathan N.; Davis, John A.; Yu, Chenglong; Hurst, Susan; Ja, Williams; Loi, Cho‐Ming

doi:10.1124/dmd.107.015230

Cited by 50 publications

(44 citation statements)

References 39 publications

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“…However, some reports about gemfibrozil's effects on UGTs are available. Goosen et al (2007) have recently reported that gemfibrozil inhibited atorvastatin lactonization and atorvastatin lactone glucuronidation with IC 50 values of 346 and Ͼ1000 M, respectively. The highest rates of lactonization or atorvastatin lactone glucuronidation were mediated by UGT1A1 and UGT1A3, or UGT1A3 and UGT1A4, respectively (Goosen et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Goosen et al (2007) have recently reported that gemfibrozil inhibited atorvastatin lactonization and atorvastatin lactone glucuronidation with IC 50 values of 346 and Ͼ1000 M, respectively. The highest rates of lactonization or atorvastatin lactone glucuronidation were mediated by UGT1A1 and UGT1A3, or UGT1A3 and UGT1A4, respectively (Goosen et al, 2007). The study by Prueksaritanont et al (2002b) showed that gemfibrozil inhibited simvastatin glucuronidation (IC 50 ϭ 354 M); simvastatin is mainly glucuronidated by UGT1A1 and UGT1A3.…”

Section: Discussionmentioning

confidence: 99%

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The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

Mano¹,

Usui²,

Kamimura³

2007

Drug Metab Dispos

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ABSTRACT:Gemfibrozil, a fibrate hypolipidemic agent, is eliminated in humans by glucuronidation. A gemfibrozil glucuronide has been reported to show time-dependent inhibition of cytochrome P450 2C8. Comprehensive assessment of the drug interaction between gemfibrozil and cytochrome P450 2C8 substrates requires a clear understanding of gemfibrozil glucuronidation. However, the primary UDPglucuronosyltransferase (UGT) isozymes responsible for gemfibrozil glucuronidation remain to be determined. Here, we identified the main UGT isozymes involved in gemfibrozil glucuronidation. Evaluation of 12 recombinant human UGT isozymes shows gemfibrozil glucuronidation activity in UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, with UGT2B7 showing the highest activity. The kinetics of gemfibrozil glucuronidation in pooled human liver microsomes (HLMs) follows Michaelis-Menten kinetics with high and low affinity components. The high affinity K m value was 2.5 M, which is similar to the K m value of gemfibrozil glucuronidation in recombinant UGT2B7 (2.2 M). In 16 HLMs, a significant correlation was observed between gemfibrozil glucuronidation and both morphine 3-OH glucuronidation (r ‫؍‬ 0.966, p < 0.0001) and flurbiprofen glucuronidation (r ‫؍‬ 0.937, p < 0.0001), two reactions mainly catalyzed by UGT2B7, whereas no significant correlation was observed between gemfibrozil glucuronidation and either estradiol 3␤-glucuronidation and propofol glucuronidation, two reactions catalyzed by UGT1A1 and UGT1A9, respectively. Flurbiprofen and mefenamic acid inhibited gemfibrozil glucuronidation in HLMs with similar IC 50 values to those reported in recombinant UGT2B7. These results suggest that UGT2B7 is the main isozyme responsible for gemfibrozil glucuronidation in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

Mano¹,

Usui²,

Kamimura³

2007

Drug Metab Dispos

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“…Because in HF diet-fed dmd.aspetjournals.org rats treated with fluvastatin for 8 days, the decrease in hepatic levels of CYP2Cs was moderate but that in CYP3As was extensive, the administration of other statins such as simvastatin, lovastatin, and atorvastatin to HF diet-fed rats might cause more severe adverse effects. The dihydroxy heptanoic or heptenoic acid side chain of statin hydroxy acids is a structural feature common to all statins, which undergo glucuronidation to form an acyl glucuronide conjugate and lactonization to form a statin hydroxy acid lactone by human UGT1A1, UGT1A3, UGT1A4, UGT1A8, UGT1A9, and UGT2B7 (Prueksaritanont et al, 2002;Goosen et al, 2007). Riedmaier et al (2010) have demonstrated that lactonization of atorvastatin is catalyzed mainly by UGT1A3 in humans and affected by polymorphisms at the UGT1A locus.…”

Section: Discussionmentioning

confidence: 99%

“…Atorvastatin, lovastatin, and simvastatin are oxidized mainly by CYP3A4 (Fischer et al, 1999) and their glucuronidation is catalyzed mainly by human UGT1A1 and UGT1A3 (Prueksaritanont et al, 2002). Although a potent inhibitor of CYP3A4 can significantly increase the plasma concentrations of the active forms of atorvastatin, lovastatin, and simvastatin, which are oxidized mainly by CYP3A4 (Kyrklund et al, 2001;Backman et al, 2002;Goosen et al, 2007), fluvastatin is oxidized mainly by CYP2C9 (Spence et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

Sugatani

Sadamitsu²,

Kurosawa³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Rats that consumed a high-fat and high-sucrose diet (HF diet) developed hepatic steatosis. Treatment of HF diet-fed rats with fluvastatin (8 mg/kg) was lethal, followed by an elevation in levels of plasma aspartate aminotransferase and creatine kinase activities and skeletal muscle toxicity. This study was conducted to determine whether nutritional status affects statin-induced adverse effects in rats. Fluvastatin treatment of rats fed the HF diet led to an increase in systemic exposure, suggesting altered metabolism and elimination. In fact, although hepatic multidrug resistance-associated protein (Mrp) 2 and multidrug resistance (Mdr) 1b protein levels were not significantly changed by fluvastatin treatment for 8 days of rats fed a HF diet, the organic anion-transporting protein (Oatp) 1, Mrp3, CYP1A, CYP2C, UDP-glucuronosyltransferase (UGT) 1A1, and UGT1A5 protein levels were moderately decreased and the Oatp2, CYP3A, and UGT2B1 protein levels were markedly suppressed. No significant difference in the baseline level of Oatp1, Oatp2, Mrp2, Mrp3, Mdr1b, CYP1A, CYP2C, CYP3A, UGT1A1, UGT1A5, or UGT2B1 protein was found between the standard diet-and HF diet-fed groups. In addition, the mRNA levels of Oatp2, CYP2C11, and CYP3A1/2 were markedly decreased in HF diet-fed and fluvastatin-treated rats. There was no significant difference in the glucuronidation activities against fluvastatin among the four groups. In liver cell nuclei, levels of constitutive androstane receptor, pregnane X receptor, and hepatocyte nuclear factor 4␣ proteins were decreased in fluvastatin-treated HF diet-fed rats, which correlated with the decrease in Oatp2, CYP2C, and CYP3A. Taken together, these results indicate that nutritional status may influence adverse effects of fluvastatin by increasing systemic exposure through modulation of hepatic uptake and elimination.

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“…Gemfibrozil 1-0-β glucuronide and, to a lesser extent, the parent compound are also potent inhibitors of OAT1B1/3-mediated hepatic uptake of statin acids, as well as OATP2B1, Na+-taurocholate cotransporting polypeptide, the renal transporter OAT3, and statin glucuronidation or lactonization. 52,53 Thus, DDIs, including hepatotoxicity and muscle-related toxicity, in patients receiving statin-gemfibrozil combination therapy may vary as a result of differences in statin susceptibility to inhibitory effects of intestinal, hepatic, and renal transporters, as well as CYP450 metabolism.…”

Section: Gemfibrozilmentioning

confidence: 99%

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

Wiggins¹,

Saseen²,

Page³

et al. 2016

Circulation

247

194

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A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs. 3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The variability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmacokinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t 1/2 ]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activity, and disease impairment affecting drug metabolism (eg, hepatic or renal impairment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy). Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information will assist clinicians in the safe prescribing of medications and permits careful consideration of the benefits and risks of concomitant medications.Statins reduce morbidity and mortality in patients with known atherosclerotic cardiovascular disease (ASCVD) and in many primary prevention patients.4-9 Current guidelines recommend high-intensity statin therapy in all patients with ASCVD age ≤75 years and moderate-to high-intensity statin therapy in patients with ASCVD and age >75 years, diabetes mellitus, and familial hypercholesterolemia and in primary prevention patients with 10-year ASCVD risk ≥7.5%.10 Given the important role of statins in patients with ASCVD and those at high ASCVD risk, combination therapy with statins and other cardiovascular medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.Another important aspect of prescribing medications in combination is evalu...

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Atorvastatin Glucuronidation Is Minimally and Nonselectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate, and Fenofibric Acid

Abstract: ABSTRACT:Gemfibrozil coadministration generally results in plasma statin area under the curve (AUC) increases, ranging from moderate (2-to 3-fold) with simvastatin, lovastatin, and pravastatin to most significant with cerivastatin (5.6-fold

Cited by 50 publications

References 39 publications

The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

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

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