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Disorders of lipid metabolism
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Fibric acid derivatives (fibrates) activate lipoprotein lipase, promote hepatic bile secretion, and reduce hepatic triglyceride production. The Helsinki Heart Study investigated gemfibrozil dosed at 600 mg twice daily in the primary prevention of heart disease in men (42). In subjects with the best adherence to treatment, gemfibrozil reduced, on average, triglycerides by 45%, total cholesterol by 14%, and LDL-C by 15%, while raising HDL-C by 14%. The lipid changes seen in the gemfibrozil group were associated with a significantly lower risk of coronary events.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Montelukast and quercetin have been receommended by the FDA as the selective inhibitors for CYP2C8 used in in vitro studies (Huang et al. 2007, 2008). Trimethoprim, gemfibrozil, rosiglitazone, and pioglitazone are acceptable inhibitors only used for in vitro studies. For in vivo inhibition studies, gemfibrozil is preferred. Mechanism-based CYP2C8 inhibitors include nortriptyline (Polasek et al. 2004), phenelzine (Polasek et al. 2004), isoniazid (Polasek et al. 2004), amiodarone (Polasek et al. 2004), desethylamiodarone (Ohyama et al. 2000), 17α-ethynylestradiol (Polasek et al. 2004), and verapamil (Polasek et al. 2004). The β-O-glucuronide of gemfibrozil is also a mechanism-based inhibitor of CYP2C8 (Ogilvie et al. 2006).
Lipoprotein Metabolism and Implications for Atherosclerosis Risk Determination and Treatment Decisions
Published in P. K. Shah, Risk Factors in Coronary Artery Disease, 2006
H. Robert Superko, Szilard Voros, Spencer King III
Low HDL-C has been identified as a cardiovascular risk factor for many years (82). One problem with attributing independent risk to low HDL-C is the powerful inverse correlation HDL-C has with other risk factors such as triglycerides and small LDL (12). This correlation issue compounds the ability to attribute CV benefit to HDL-C change since most lifestyle and pharmacologic therapies that increase HDL-C also reduce body fat, triglycerides, small LDL, and IDL, each of which is associated with CV risk. Thus, it is often unclear if it is the HDL-C increase that causes the benefit or the triglyceride and small LDL reduction, or a combination of the two. Evidence that HDL-C raising is of CV benefit was presented with the results of the VA-HIT results (83). In this investigation, men with relatively low HDL-C were randomized to gemfbrozil or a placebo and the resulting reduction in CV events was statistically attributed to an increase in HDL-C, which was attributed to gemfibrozil therapy. However, the issue of which parameter was responsible for the cardiovascular benefit remains unclear since gemfibrozil treatment reduces triglycerides and small LDL as well as increases HDL-C (84). From a clinician’s standpoint, the argument of statistical independence is less important since clinical trials using combination drug therapy, which both lowers LDL-C, small LDL, and IDL and increases HDL-C and HDL2, have demonstrated both clinical event and arteriographic benefit (76,77).
Power of integrating PBPK with PBBM (PBPK-BM): a single model predicting food effect, gender impact, drug-drug interactions and bioequivalence in fasting & fed conditions
Published in Xenobiotica, 2023
Rajkumar Boddu, Sivacharan Kollipara, Gautam Vijaywargi, Tausif Ahmed
Similarly, dosage regimen of Gemfibrozil 600 mg BID administered over 7 days and API administered 40 mg SD on day 7 adopted to study transporter inhibitory effect. Along with gemfibrozil, its metabolite gemfibrozil 1-0-beta-glucuronide can also inhibit OATP1B1 and hence is considered for DDI evaluation. Transporter OATP1B1 inhibitory kinetic parameters like Ki:68.05 µM (for gemfibrozil) and 9.3 µM (for glucuronide metabolite) were taken from literature and used for DDI effect with API (Nakagomi-Hagihara et al. 2007; Karlgren et al. 2012). The enzyme kinetic parameters are detailed in Table 1. After integration of the respective PBPK models, DDI impact was evaluated and compared against the reported values to further prove the model applicability as to DDI impact.
Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia
Published in Expert Opinion on Investigational Drugs, 2023
Victoria Profeta, Kellie McIntyre, McKenzie Wells, Courtney Park, David R Lynch
Drug interactions of omaveloxolone with other specific medications have been empirically tested in one study. The Phase I study population consisted of healthy volunteers in a parallel assignment intervention model [97]. In part I, single doses of the following medications were administered to the subjects while taking 150 mg of omav: Midazolam, Repaglinide, Metformin, Rosuvastatin, and Digoxin. Part two tested subjects taking 150 mg of omav on day 1 through 13 and 600 mg of gemfibrozil twice a day on day 10 through 18. Part 3 studied participants taking omav on day 1 through 13 and itraconazole day 10 through 18. Part 4 studied subjects taking omav on day 1 through 13 and verapamil on day 10 through 18 [97]. There are currently no results published in this study, but they may be important to the practical use of omaveloxolone in FRDA.
Targeting triglycerides to lower residual cardiovascular risk
Published in Expert Review of Cardiovascular Therapy, 2022
Kristen J. Bubb, Adam J. Nelson, Stephen J. Nicholls
Fibric acid derivatives are modest agonists of peroxisome proliferator activated receptor-α (PPAR-α) with the ability to lower triglyceride levels by up to 25%, in addition to mild effects on LDL-C and HDL-C levels [29]. Fibrates decrease expression of apoC3, an inhibitor of lipoprotein lipase, and direct upregulation of both lipoprotein lipase and fatty acid oxidation, leading to reduced hepatic lipogenesis [29]. Early clinical trials with gemfibrozil have demonstrated reductions in cardiovascular risk in both the primary and secondary prevention setting [30,31]. Subsequent studies with fenofibrate, conducted with greater background use of statin therapy, failed to demonstrate cardiovascular benefit [32,33]. Meta-analyses of fibrate trials demonstrated that the cardiovascular benefit of fibrates appears to be greatest in the patient with baseline hypertriglyceridemia, identifying the patients most likely to benefit from their use [34].