China
Africa
Explore chapters and articles related to this topic
Inhibitors of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Halofantrine inhibits CYP2D6-dependent 1′-hydroxylation of bufuralol with a Ki of 4.3 μM (Figure 4.12) (Halliday et al. 1995). It appears that halofantrine competes for the substrate-binding site of CYP2D6 (Otton et al. 1988). Dexmedetomidine, the pharmacologically active optical dextro isomer of medetomidine, which is a highly selective α2-adrenergic receptor agonist with potent sedative, analgesic, and anesthetic effects, inhibits CYP2D6-dependent dextromethorphan O-demethylation with an IC50 of 1.8 μM (Rodrigues and Roberts 1997). In addition, dalcetrapib inhibits CYP2D6 with an IC50 of 82 μM, but it does not affect the activity of CYP2D6 in vivo (Derks et al. 2009).
Pharmacology of p-sitosterol and other Sterols
Published in Amritpal Singh Saroya, Contemporary Phytomedicines, 2017
A recent trial with dalcetrapib (Fig. 19.7), a cholesteryl esterase transport protein (CETP) inhibitor. Cholesteryl esterase transport protein inhibitor is a new class of cholesterol lowering medications currently in development. It showed that this agent may have the potential to increase levels of campesterol through increasing intestinal absorption. Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis (Niesor et al. 2011).
Myths of Cholesterol
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2015
Jonny Bowden, Stephen T. Sinatra
After 2 years, the niacin group experienced a significant increase in plasma HDL-C but no improvement in patient survival. (The safety board halted the trial.) The dal-OUTCOMES study45 randomized patients to either standard of care plus placebo or standard of care plus dalcetrapib, a CETP (cholesterylester transfer protein) inhibitor. (Inhibition of the CETP pathway, which facilitates transfer of triglyceride (TG) and cholesterol ester between lipoproteins, can increase concentrations of HDL-C.) Over the course of the trial, HDL-C levels increased from baseline by 4%–11% in the placebo group and by 31%–40% in the dalcetrapib group. At a prespecified interim analysis, the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point and did not have a significant effect on any component of the primary end point or on total mortality.
Pharmacogenomics in the era of next generation sequencing – from byte to bedside
Published in Drug Metabolism Reviews, 2021
Laura E. Russell, Yitian Zhou, Ahmed A. Almousa, Jasleen K. Sodhi, Chukwunonso K. Nwabufo, Volker M. Lauschke
Another interesting example is the use of pharmacogenomic biomarkers for predicting the outcomes of dalcetrapib therapy. Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that increased HDL cholesterol but failed to reduce the risk of recurrent cardiovascular events in a large phase 3 trial of 15,871 acute coronary syndrome patients (Schwartz et al. 2012). However, a subsequent GWAS study in the discovery cohort of the trial with 5,749 participants identified genetic variations in ADCY9 that are significantly associated with dalcetrapib cardiovascular endpoints (p = 2.1*10−8; HR = 0.61 (Tardif et al. 2015)). Interestingly, in mice, Adcy9 ablation reduced atherosclerosis upon high cholesterol feeding, but these positive effects were lost upon transgenic introduction of CETP, thus corroborating a direct functional link between ADC9 and CETP function as well as cardiovascular outcomes (Rautureau et al. 2018). However, this association was not supported in 19,210 genotyped individuals of European ancestry treated with the CETP inhibitor anacetrapib, suggesting that effects might be drug-specific or dependent on additional factors yet to be identified (Hopewell et al., 2019).
The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats
Published in Xenobiotica, 2021
Hiroaki Takubo, Tomohiro Ishikawa, Toshio Taniguchi, Kazunori Iwanaga, Yukihiro Nomura
Until now, some thiols including captopril, tiopronin and N-acetylcysteine have been investigated and approved. Although these sulfhydryl compounds form covalent bonds with plasma proteins, it has been demonstrated that the covalent disulfide bond is reversible (Harada et al., 2002; Park et al., 1982). However, it has not been fully investigated whether these compounds accumulate in the body. Based on an in vitro study, Algaier et al. (2008) reported that the active metabolite of prasugrel, which has a thiol group, binds irreversibly to the target protein via a disulfide bond. Campbell et al. (2005) also reported that a large dose of N-acetylcysteine did not reduce the inhibitory effect of clopidogrel on platelet aggregation in vitro or in vivo, indicating that active metabolites of these drugs may bind irreversibly to target proteins. Takubo et al. (2014) have previously demonstrated the reversibility of the disulfide bond between the dalcetrapib active form and thiols using in vitro and in vivo studies. There is also little information on the accumulation of sulfhydryl compounds in the body during multiple administration. This lack of information about accumulation may be a factor that prevents the application of the covalent inhibitor approach in drug development. The objective of this study was to investigate the accumulation of dalcetrapib during multiple oral administration in rats, which is used in toxicity studies.
The mystery of evacetrapib - why are CETP inhibitors failing?
Published in Expert Review of Cardiovascular Therapy, 2020
Stephen J. Nicholls, Kristen Bubb
Dalcetrapib is a modest CETP inhibitor, raising HDL cholesterol by up to 30% and with no discernible impact on LDL cholesterol levels. Small clinical trials established no increase in vascular inflammation or presence of endothelial dysfunction with dalcetrapib, suggesting a lack of torcetrapib like toxicity [21,22]. A large clinical outcomes trial was stopped due to clinical futility [12]. A post hoc pharmacogenomic analysis of this trial revealed that patients carrying the AA rs1967309 polymorphism of adenylate cyclase 9 on chromosome 16 demonstrated less cardiovascular events in the dalcetrapib group, associated with greater increases in ex vivo cholesterol efflux capacity and a lack of increase in inflammatory markers, compared with dalcetrapib treated patients without this polymorphism [23]. This has led to a new cardiovascular outcomes trial performed exclusively in patients with this polymorphism [24].