Polymorphisms

Schaffenburg, William; Lockshin, Benjamin; DeKlotz, Cynthia M. C.

doi:10.1016/b978-0-323-61211-1.00003-6

Cited by 10 publications

(6 citation statements)

References 66 publications

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“…CYP2A6 metabolizes nicotine (the primary psychoactive component in cigarettes), cotinine, tegafur, letrozole, coumarin, methoxyflurane, efavirenz, valproic acid, pilocarpine, artemisinin, artesunate, caffeine, disulfiram, halothane, fadrozole and tyrosol, 40,41 whereas CYP3A4 is responsible for 40% to 45% of all phase I metabolism and approximately 70% of gastrointestinal CYP activity beside being co-expressed with P-glycoprotein (PGP) in the liver and intestines. 42,43 CYP3A4 metabolizes drugs such as paclitaxel, fentanyl, tamoxifen, tacrolimus and statins. 40 Therefore, khat/cathine users who are on medications metabolized by CYP2A6 and CYP3A4 may experience herb-drug interactions or may fail to respond to some medications.…”

Section: Discussionmentioning

confidence: 99%

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

et al. 2022

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Cathine is the stable form of cathinone, the major active compound found in khat ( Catha edulis Forsk) plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities in vitro and in vivo. With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput in vitro fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs’ active sites. The half maximal inhibitory concentration (IC50) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in Ki analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with Ki value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and in vitro outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4.

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Section: Discussionmentioning

confidence: 99%

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

et al. 2022

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“…On the contrary, in the Caucasian subgroup, the CYP2C9*2 carriers, such as CYP2C9*1/*2 and CYP2C9*2/*2, were more common than in the Asian subgroup. The ethnic difference in the MD by CYP2C9 polymorphisms is possibly due to different distributions of *2 and *3 , considering that the CYP2C9*3 allele has lower enzyme activity than the CYP2C9*2 allele [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of CYP2C9 Genetic Polymorphisms on the Pharmacokinetics of Losartan and Its Active Metabolite E-3174: A Systematic Review and Meta-Analysis

Park

Song

Yee

et al. 2021

JPM

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This study aimed to investigate the influence of CYP2C9 genetic polymorphisms on the pharmacokinetics of losartan and its active metabolite, E-3174, through a systematic review and meta-analysis. Eight studies published before March 2021 were included in this study. We used PubMed, the Cochrane Library, EMBASE, and Web of Science, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The data analysis was conducted through Review Manager (RevMan), version 5.3, and R software. We found that healthy volunteers with CYP2C9*2 or *3 carriers had higher area under the curve (AUC0-∞) of losartan (mean difference (MD) 0.17 μg·h/mL; 95% confidence intervals (CI): 0.04, 0.29) and lower AUC0-∞ of E-3174 (MD −0.35 μg·h/mL; 95% CI: −0.62, −0.08) than those with CYP2C9*1/*1. Subjects with CYP2C9*2 or *3 carriers showed lower maximum concentration (Cmax) of E-3174 than those with CYP2C9*1/*1 (MD −0.13 μg/mL; 95% CI: −0.17, −0.09). For half-life, subjects with CYP2C9*2 or *3 carriers had longer half-lives of losartan and E-3174 than those with CYP2C9*1/*1 (MD 0.47 h; 95% CI: 0.32, 0.61 and MD 0.68 h; 95% CI: 0.44, 0.92, respectively). This meta-analysis suggests that the pharmacokinetics of losartan and E-3174 are associated with the CYP2C9 polymorphisms

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“…Cytochrome P450 family 2 subfamily C member 9 or CYP2C9*1*3 is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. The CYP2C9*1*3 genotype, which has been associated with reduced aldosterone response to captopril ( 51 ), has been described in 4% of Chinese and Japanese populations in contrast to Caucasian populations, which tend to harbor different CYP2C9 alleles ( 52 ).…”

Section: Diagnostic Accuracy Of Cct Compared To Other Confirmatory Testsmentioning

confidence: 99%

Captopril challenge test: an underutilized test in the diagnosis of primary aldosteronism

Jahan,

Yang,

et al. 2024

Endocrine Connections

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Primary aldosteronism (PA) is the most common cause of endocrine hypertension and is often underdiagnosed. This condition is associated with increased cardiovascular morbidity and mortality in comparison to age and blood pressure matched individuals with essential hypertension (EH). The diagnostic pathway for PA consists of three phases: screening, confirmatory testing, and subtyping. The lack of specificity in the screening step, which relies on the aldosterone to renin ratio, necessitates confirmatory testing. The Endocrine Society’s clinical practice guideline suggests four confirmatory tests, including the fludrocortisone suppression test (FST), saline suppression test (SST), captopril challenge test (CCT), and oral sodium loading test (SLT). There is no universally accepted choice of confirmatory test, with practices varying among centers. The SST and FST are commonly used, but they can be resource-intensive, carry risks such as volume overload or hypokalemia, and are contraindicated in severe/uncontrolled HTN as well as in cardiac and renal impairment. In contrast, CCT is a safe and inexpensive alternative that can be performed in an outpatient setting and can be applied when other tests are contraindicated. Despite its simplicity and convenience, the variability in captopril dose, testing posture and diagnostic threshold limit its widespread use. This narrative review evaluates the diagnostic accuracy of the CCT across different populations, addresses controversies in its usage, and proposes recommendations for its use in the diagnosis of PA. Furthermore, suggestions for future research aimed at promoting the wider utilization of the CCT as a simpler, safer and more cost-effective diagnostic test are discussed.

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Polymorphisms

Cited by 10 publications

References 66 publications

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

Influence of CYP2C9 Genetic Polymorphisms on the Pharmacokinetics of Losartan and Its Active Metabolite E-3174: A Systematic Review and Meta-Analysis

Captopril challenge test: an underutilized test in the diagnosis of primary aldosteronism

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