The rise of genomics and personalized medicine
Priya Hays in Advancing Healthcare Through Personalized Medicine, 2017
The other issue is that CYP2C19 doesn’t affect only Plavix. It affects many other drugs. Patients who are *2/*2 don’t metabolize the antidepressant Selexa [like] normal people. When they don’t metabolize it well, they develop higher drug concentrations, and they actually have a better response because Selexa is the active drug. It’s not just drug–gene pairs: it is many, many genetic variants. Some of them apply to many drugs. A famous gene, CYP2D6, has a protein product which metabolizes a quarter of the widely used drugs in the world. Seven percent of the Caucasian and African populations have an abnormal copy of the gene; there are literally hundreds of variants in the CYP2D6 gene that can cause loss of function effects (Personal communication, Dan Roden, 2014).
Structure and function of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
CYP2D6 is an important enzyme since it can metabolize approximately 25% of clinical drugs and is subject to polymorphism with significant clinical consequences. There are several properties that determine the metabolism of any substrate by CYP2D6. These include (a) the topography of the active site, (b) steric interactions between the ligand and the activesite pocket, and (c) key electronic interactions. The elucidation of its crystal structure has provided very useful information on how ligands (e.g., substrates or inhibitors) interact with this enzyme and how CYP2 members determine their substrate specificity. However, the resolved structure of CYP2D6 (PDB entry: 2F9Q) is ligand free, and thus how and whether ligand binding induces changes in size, shape, and hydration of the active site are unknown. It is necessary to resolve and obtain the structures of CYP2D6 in complex with a substrate or inhibitor to better understand how ligands interact with CYP2D6 and how such interactions affect the rationalization and prediction of the catalytic activity, ligand specificity, and regiospecific metabolism of this important enzyme.
The Precision Medicine Approach in Oncology
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of drugs used in the direct (e.g., tamoxifen) or indirect (e.g., ondansetron, codeine, dextromethorphan, tramadol) treatment of cancer are metabolized by the enzyme CYP2D6, and the activity of this enzyme in individuals can affect the dose of drug required. Roche developed a device known as the AmpliChipTM (Figure 11.31) which was based on microarray technology from Affymetrix Inc (i.e., the GeneChipTM). Approved for in vitro diagnostic use in the US and EU in 2004, the AmpliChipTM device is no longer available having been superseded by tests from other companies. However, it was significant in being the first FDA-approved pharmacogenetic test, and so is described below.
Cannabidiol drug interaction considerations for prescribers and pharmacists
Published in Expert Review of Clinical Pharmacology, 2022
Myfanwy Graham, Jennifer H Martin, Catherine J Lucas, Bridin Murnion, Jennifer Schneider
Many commonly prescribed drugs are metabolized by the CYP enzymes and may be candidates for drug–drug interactions with cannabidiol. For example, CYP3A4 is involved in the metabolism of about a quarter of all commonly used drugs and inhibition of CYP3A4 may increase serum concentrations of macrolides, calcium channel blockers, benzodiazepines, cyclosporine, sildafenil, antihistamines, haloperidol, antiretrovirals, and some statins. CYP2D6 metabolizes many antidepressants and inhibition has the potential to increase serum concentrations of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, beta-blockers, and opioids such as codeine and oxycodone [27]. Some standard drug interaction checking platforms do not distinguish between minor and major CYP metabolic pathways and clinical significance data is not readily available for many potential cannabidiol interactions.
Characterization of in vitro and in vivo metabolism of leelamine using liquid chromatography-tandem mass spectrometry
Published in Xenobiotica, 2019
Riya Shrestha, Jung Jae Jo, DooHyun Lee, Taeho Lee, Sangkyu Lee
The CYP2D6 enzyme metabolizes more than 20% of clinically used drugs and exhibits high polymorphism that is used to categorize the population, according to the degree of activity of the enzyme, as poor, intermediate, extensive, and ultrarapid metabolizers (PM, IM, EM, and UM, respectively) (Bernard et al., 2006). The genetic polymorphism of CYP2D6 differs widely among different ethnicities and has varying effects on drug metabolism by the enzyme. Adverse drug effects or therapeutic loss could develop because of CYP2D6 polymorphisms (Ingelman-Sundberg, 2005; Zanger & Schwab, 2013). One notable example of the effect of CYP2D6 polymorphism on drug metabolism is that on tamoxifen. CYP2D6 metabolizes tamoxifen, a leading chemotherapeutic drug for breast cancer, to its active form endoxifen. However, patients with a PM status fail to respond to the drug, causing a high relapse rate of the disease (Beverage et al., 2007). Similarly, in this study, we found that leelamine is highly metabolized to its hydroxylated form by a CYP2D6 isoform. It is likely that the metabolic profile of leelamine in humans could exhibit interindividual variation. Therefore, acute research studies should be performed to determine the leelamine dose that shows effective therapeutic activity.
Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Nehad M. El-Dydamony, Rana M. Abdelnaby, Rasha Abdelhady, Omaima Ali, Mohamed I. Fahmy, Rasha R. Fakhr Eldeen, Amira A. Helwa
Since the biological activity of a given drug is a function of its physicochemical properties as they affect its ability to reach its biological target in reasonable concentration, it was important to determine these ADMET parameters for the newly discovered pyrimidine derivative 7f using Discovery Studio version 3.0 suite. The presented data in Table 10 demonstrated that 7f obeys Lipinski’s rule of five which gives an indication about its drug-likeness. It has a Log P of 5 that may reflect on the low solubility, absorption levels and enhances the blood–brain barrier penetration. Additionally, it has plasma proteins binding ability due to its lipophilicity which will affect its duration of action, half-life, and elimination. Also, it was estimated that it is not a substrate for CYP2D6 therefore there will probably not be drug–drug interactions. Finally, the AMES and hepatotoxicity prediction suggested its safety50,51.
Related Knowledge Centers
- Central Nervous System
- Clearance
- Enzyme
- Functional Group
- Xenobiotic
- Metabolism
- Liver
- Cytochrome P450
- Gene
- Substantia Nigra