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Precision medicine in coronary artery disease
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Melvin George, Luxitaa Goenka, Sandhiya Selvarajan
Presently the website WarfarinDosing.org is available to help clinicians to begin warfarin therapy by evaluating the required therapeutic dose among patients who are new to warfarin therapy. The evaluation is based on the patient's clinical and demographic factors. The genotypes of two genes—cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1)—are also evaluated.
Sulfonamides
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Natasha E. Holmes, M. Lindsay Grayson
Some of the sulfonamides are converted to inactive metabolites in the liver by glucuronidation. This process is particularly marked with sulfadimethoxine, 80% of which is excreted as a very soluble glucuronide in the urine (Busch and Lane, 1967). Sulfamethoxazole undergoes N4-hydroxylation in humans predominantly via the cytochrome P450-2C9 subfamily (Cribb et al., 1995). A sequence of reactions forms reactive metabolites responsible for mediating hypersensitivity reactions.
Future directions in stroke treatment
Published in Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees, Stroke in Practice, 2017
Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees
Warfarin is metabolised by the cytochrome P450 2C9 enzyme (CYP2C9) into its major inactive metabolite, 7-hydroxywarfarin (seeFigure 11.1).26 Genome-wide association studies (GWAS) have identified genetic polymorphisms of CYP2C9 as an important determinant of warfarin activity.27 The two common allelic variants, CYP2C9*2 and CYP2C9*3, result in poor metaboliser (PM) phenotypes and display reduced warfarin metabolism.28 These patients’ genotypes have been shown to have an increased risk of overcoagulation and haemorrhagic complications.2930 The therapeutic target for warfarin, Vitamin K epoxide reductase complex 1 (VKORC1), also displays genetic polymorphism and pharmacogenetic variability.27, 31 These mutations have been associated with both warfarin resistance and increased drug sensitivity.32 There has therefore been increasing interest in the role of genotype-guided warfarin therapy in clinical practice.33 The FDA approved warfarin genotype-testing in 2007 and has recently updated its label for warfarin pharmacogenetic testing (www.pharmgkb.org/clinical/warfarin.jsp). Various PCR-based genotyping methods are now available and some have been approved by the FDA.3435
A translational strategy employing physiologically based modelling to predict the pharmacological active dose of RO7119929, an oral prodrug of a targeted cancer immunotherapy TLR7 agonist
Published in Xenobiotica, 2022
Caroline Rynn, Kenichi Umehara, Tianyi Jiang, Malika Ait-Goughoulte, Neil Parrott
The active drug selectively binds to TLR7 with high potency (the EC50 was 48 nM in HEK293 cell lines genetically engineered to overexpress human TLR7 reporter cells) whereas the potency of prodrug was ∼200-fold lower. Structures of prodrug and active drug are presented in Figure 1. Preclinical characteristics of the prodrug and active drug were determined early in the project from which we developed our hypothesis of a liver-targeting approach for the active drug. The prodrug was designed as a Biopharmaceutics Classification System (BCS) class 1 molecule with high solubility and high permeability, and this was expected to confer good oral absorption (Amidon et al. 1995). In preclinical models, absorption of the prodrug was fast with almost complete conversion of prodrug to the active drug during first pass. Data generated in human in vitro systems indicated that metabolism would occur principally in the liver, predominantly by cytochrome P450 2C9 and 2C19. The active drug falls into the BCS class 4 with low permeability and is also a substrate of human OATP1B1 transporter, potentially prolonging the duration of pharmacological effect at the target site. This was supported by a high measured liver:plasma partitioning (Kp >5) in rat following oral dosing of the prodrug.
The role of sulfonylureas in the treatment of type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2022
Brian Tomlinson, Nivritti Gajanan Patil, Manson Fok, Paul Chan, Christopher Wai Kei Lam
Most of the sulfonylureas are metabolized by cytochrome p450 2C9 (CYP2C9) with a contribution from CYP2C19 or CUP3A4 for some drugs, and some have active metabolites (Table 1). Two variants in CYP2C9 associated with reduced enzyme activity, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) were associated with a greater response to sulfonylureas in an analysis from the Go-DARTS study [134]. This effect would be similar to giving an increased dose of the drug so may not have an advantage in the long run and may be more important in relation to the adverse effect of hypoglycemia [135,136]. This may also be relevant for drug interactions when other drugs inhibiting CYP2C9 or CYP2C19 are given [137,138].
Reckoning γ-Glutamyl-S-allylcysteine as a potential main protease (mpro) inhibitor of novel SARS-CoV-2 virus identified using docking and molecular dynamics simulation
Published in Drug Development and Industrial Pharmacy, 2021
Arun Parashar, Arpit Shukla, Ankush Sharma, Tapan Behl, Dweipayan Goswami, Vineet Mehta
In our study, we used the pkCSM - pharmacokinetics server [47] for predicting the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the top hits (Chloroquine, Cuscohygrine, γ-Glutamyl-S-allylcysteine, Anahygrine and S-allylcystein). This server predicted physiochemical as well as pharmacological properties. Simplified Molecule Input Line Entry Specification (SMILES) of the selected molecules were retrieved from PubChem, followed by uploading them to pkCSM - pharmacokinetics server. The server computed in-vivo absorption parameters like water solubility in the buffer system (SK atomic types, mg/L), Human intestinal absorption (HIA, %), in-vivo Caco2 cell permeability (Human colorectal carcinoma), in-vivo skin permeability (logKp, cm/hour), and in-vivo P-glycoprotein inhibition. We determined the metabolic parameters by using in-vivo Cytochrome P450 2C9 inhibition, in-vivo Cytochrome P450 2C19 inhibition, in-vivo Cytochrome P450 2D6 inhibition, in-vivo Cytochrome P450 3A4 inhibition, in-vivo Cytochrome P450 2D6 substrate, and in-vivo Cytochrome P450 3A4 substrate. For the distribution properties we included tests like, Blood-Brain Barrier (BBB) penetration, Central Nervous System (CNS) permeability and Lipinski’s Rule (Rule of Five). To access the toxicity of compounds, a range of vital endpoints such as, ames test, acute algae toxicity, 2 years carcinogenicity bioassay in rat, 2 years carcinogenicity bioassay in mouse, in-vivo Ames test result in TA100 strain (Metabolic activation by rat liver homogenate) were computed. Moreover, many drugs are often withdrawn at clinical trial stages due to their poorer renal clearance, which makes excretion a very important parameter. Therefore, in this study we also included total renal clearance and renal OCT2 Substrate to identify the excretion efficacy of the molecules under study.