Ayurveda Renaissance – Quo Vadis?
D. Suresh Kumar in Ayurveda in the New Millennium, 2020
Ghodke et al. (2011) studied the gene polymorphism of the CYP2C19 gene involved in metabolism of many drugs (Goldstein and de Morais 1994: Daly 1995) in 132 unrelated healthy subjects. Significant association was observed between CYP2C19 genotype and major classes of prakṛti types. The extensive metabolizer (EM) genotype (∗1/∗1, ∗1/∗2, ∗1/∗3) was found to be predominant in pitta prakṛti (91%). Genotype (∗1/∗3) specific for EM group was present only in pitta prakṛti. The poor metabolizer (P.M.) genotype (∗2/∗2, ∗ 2/∗3, ∗3/∗3) was highest (31%) in kapha prakṛti when compared with vāta (12%) and pitta prakṛti (9%). Genotype (∗2/∗3) which is typical of the P.M. group was significant in kapha prakṛti. The authors observed interesting correlations between CYP2C19 genotypes and prakṛti, with fast and slow metabolism being one of the major distinguishing and differentiating characteristics.
Inhibitors of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Lansoprazole is more potent (Ki = 44.7 μM) than omeprazole (Ki = 240.7 μM) as an inhibitor of CYP2D6-mediated conversion of dextromethorphan to dextrorphan (Figure 4.12) (Ko et al. 1997). Mexiletine competitively inhibits dextro-methorphan O-demethylation in human liver microsomes, and propafenone, oxprenolol, propranolol, and ajmaline inhibit the CYP2D6-mediated formation of hydroxymethylmexiletine and p-hydroxymexiletine from mexiletine (Figure 4.12) (Broly et al. 1990). Omeprazole inhibits CYP2D6-dependent 1′-hydroxylation of bufuralol with a Ki of 302 μM (VandenBranden et al. 1996). Several clinical studies have shown that omeprazole has no clinically important inhibitory effect on the clearance of drugs such as metoprolol (Andersson et al. 1991) and propranolol (Henry et al. 1987), which are partially metabolized by CYP2D6. Omeprazole seems to be a particularly selective inhibitor of CYP2C19, and it has a weak interaction with CYP2D6.
Future directions in stroke treatment
Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees in Stroke in Practice, 2017
Clopidogrel is being increasingly used in the treatment of acute coronary syndrome and in secondary stroke prevention therapy. One of its important treatment indications is in reducing the risk of coronary artery stent thrombosis, post-percutaneous coronary intervention (PCI). There has been major interest in the effect of CYP2C19 pharmacogenetics on the antiplatelet activity of clopidogrel.44 Clopidogrel is a prodrug, which is metabolised by the CYP2C19 enzyme into its active metabolite (seeFigure 11.2). This irreversibly inhibits the P2Y12 receptor on the platelet surface, which subsequently blocks the activation of the GpIIb/IIIa pathway that is associated with the cross-linking of platelets via fibrin.45 Drugs that inhibit CYP2C19 enzyme function have been shown to reduce clopidogrel activation. Some commonly used proton pump inhibitors have been associated with reduced clopidogrel efficacy, and current clinical guidelines recommend avoiding these drug combinations.4647
Impact of single nucleotide polymorphisms (R132Q and W120R) on the binding affinity and metabolic activity of CYP2C19 toward some therapeutically important substrates
Published in Xenobiotica, 2020
Sayed M. Derayea, Hirofumi Tsujino, Yukiko Oyama, Yoshinobu Ishikawa, Taku Yamashita, Tadayuki Uno
In this work CYP2C19WT and two of its SNP mutants (W120R, and R132Q) were prepared. Two antidepressants (amitryptiline and imipramine) and two proton pump inhibitors (omeprazole and lansoprazole) were selected for the investigations. These drugs are good substrates for CYP2C19 and were chosen to be in pairs. Each pair has a very similar chemical structures and is metabolized at the same position as illustrated by arrows in Figure 1. Thus the effect of small modification in the chemical structure on the metabolic behavior of the substrate could be outlined. The drug binding to the CYP protein is an initial step in its metabolism. The binding affinities of the prepared CYP2C19 WT and SNP mutants toward selected drugs were deeply investigated using different techniques. Resonance Raman and UV–VIS spectroscopy were utilized to explore the effect of drug binding on the polarity of the enzyme’s active site. In addition, the enzyme activity was investigated by studying the enzyme kinetics of the CYP2C19 with the selected drugs in order to find whether the mentioned SNP mutations have any impact on the drug binding affinity and/or drug-metabolizing activity of the enzyme. Moreover, the mechanism of drug metabolism of CYP2C19 could be explained at the molecular level.
Antiretroviral treatment for HIV infection: Swedish recommendations 2019
Published in Infectious Diseases, 2020
Jaran Eriksen, Christina Carlander, Jan Albert, Leo Flamholc, Magnus Gisslén, Lars Navér, Veronica Svedhem, Aylin Yilmaz, Anders Sönnerborg
Antiplatelet agents: Clopidogrel undergoes bioactivation through CYP metabolism (CYP2C19). The concentration of active metabolites and thereby the antiplatelet activity may therefore be reduced in co-treatment with boosted PI and elvitegravir. However, atazanavir given without booster probably does not significantly affect these medicines. In contrast, the concentration of ticagrelor (metabolized mainly through CYP3A) increases greatly, leading to increased risk of bleeding. The combination of boosted PI or elvitegravir with ticagrelor is therefore contraindicated. In co-treatment with inducers (e.g. efavirenz) the effect is the opposite (reduced exposure to ticagrelor). The exposure to prasugrel, although bioactivated by CYP enzymes, is not significantly affected in co-treatment with a potent CYP3A-inhibitor (ketoconazole) or strong inducer (ritonavir), and should therefore be possible to give with all recommended ART. The following ARVs can be administered without dose adjustments:○ With prasugrel: no clinically significant interactions expected with recommended ART○ With clopidogrel: all NRTIs, dolutegravir, raltegravir, atazanavir without ritonavir, rilpivirine○ With ticagrelor: all NRTIs, dolutegravir, raltegravir, rilpivirine
Approaches to de-escalation of antiplatelet treatment in stabilized post-myocardial infarction patients with high ischemic risk
Published in Expert Review of Cardiovascular Therapy, 2022
Placido Maria Mazzone, Dominick J. Angiolillo, Davide Capodanno
POPULAR GENETICS was an open-label, noninferiority and superiority trial investigating the efficacy and safety of CYP2C19 genotype-guided selection of P2Y12 inhibitor versus standard DAPT (with prasugrel or ticagrelor) in 2,488 patients with STEMI undergoing PCI [47]. In patients randomized to the genotype-guided group, CYP2C19 genotyping was performed after PCI at a median of 1 day. Therefore de-escalation, if any, occurred after a very short period of standard DAPT at variance with previous trials. Carriers of a LoF CYP2C19 allele (*2/*3) were prescribed ticagrelor or prasugrel, while noncarriers (*1/*1) were prescribed clopidogrel. This first co-primary endpoint, a composite of all-cause death, stroke, myocardial infarction, definite stent thrombosis, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months, occurred in 5.1% of patient in the genotype-guided group and in 5.9% of patients in the standard DAPT group, meeting criteria for noninferiority (absolute difference, −0.7%; 95% CI, −2.0 to 0.7; P < 0.001 for noninferiority) but not for superiority. The second co-primary endpoint was a composite of PLATO major or minor bleeding at 12 months, which occurred significantly less in the genotype-guided group (9.8% vs 12.5%; HR, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). There were no significant differences between the two groups in the thrombotic/ischemic components of the two co-primary endpoints, with the exception of significantly less PLATO minor bleeding in the genotype-guided group.
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