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General Discussion about Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Minimizing interindividual variability in drug exposure is an important goal in drug development and discovery (Gibbs et al. 2006). CYP2D6 is considered one of the most important CYPs, with substrate specificity typical of many new chemical entities (i.e., lipophilic bases). An estimated 20% to 30% of all drugs in clinical use are metabolized at least in part by CYP2D6. The primarily hepatic expression of this enzyme governs the first-pass metabolism of many orally administered drugs, whereas the low levels of intestinal expression do not appear to be important (Madani et al. 1999).
Pain and psychiatry
Published in Ad (Sandy) Macleod, Ian Maddocks, The Psychiatry of Palliative Medicine, 2018
Ad (Sandy) Macleod, Ian Maddocks
Initially isolated from opium in 1832, codeine’s active component is predominantly morphine. Codeine is a prodrug; the breakdown to morphine by the cytochrome P450 enzyme 2D6 cannot occur in about 10% of the population (those who lack this enzyme). Others possess an ultrafast metabolising variant of CYP2D6. These pathways are blocked by SSRIs (except citalopram). The pharmacokinetics of codeine is unpredictable. Deaths have occurred in children under conventional doses because of the genetic variability in metabolism.76 Very widely used in mild to moderate pain, and often available over the counter, codeine’s use as an analgesic and anti-diarrhoea agent is limited, especially in palliative medicine.
Natural Deaths
Published in John M. Wayne, Cynthia A. Schandl, S. Erin Presnell, Forensic Pathology Review, 2017
John M. Wayne, Cynthia A. Schandl, S. Erin Presnell
Answer B is incorrect. CYP2D6 is the gene that encodes for the cytochrome p450 system in the liver that is responsible for metabolism of many drugs. Polymorphism in this gene can cause people to metabolize drugs more quickly (ultra-rapid metabolizers) or more slowly (poor metabolizers). Currently, there are no known gross or microscopic findings associated with CYP2D6 variations. The variations can only be confirmed by molecular methods.
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.
Tafenoquine for the treatment of Plasmodium vivax malaria
Published in Expert Opinion on Pharmacotherapy, 2022
Alejandro Llanos-Cuentas, Paulo Manrrique, Angel Rosas-Aguirre, Sonia Herrera, Michelle S. Hsiang
The antimalarial activity of 8-aminoquinolines is mediated through CYP2D6-dependent activation, and poor and intermediate metabolizer CYP2D6 genotypes have been associated with therapeutic failure [6,43,44]. CYP2D6 activity is measured by challenging individuals with a probe substrate, and classification into one of four metabolizer phenotypes [43]. Phenotypes can also be predicted based on the allelic type of the CYP2D6 coding gene. There are over 150 CYP2D6 variants that vary across ethnic groups [43,45]. Globally, the most common CYP2D6 variant allele of functional importance is the splice variant CYP2D6*4 (rs3892097) which is abundant in Latin America and the Caribbean [46]. In Colombia, the prevalence of CYP2D6*4 has been found to be high at 19.4%, with the prevalence of poor metabolizers to be 6.6% [47]. In South Asia, CYP2D6*10 is the main loss of function allele with prevalence reported at 19.1% [48]. Variants are classified into four functional groups. But, as many of the variants contribute, in part or entirely, to altered rates of CYP2D6-mediated drug metabolism [49,50], an activity score system was developed for translating CYP2D6 genotype to phenotype. Several studies have demonstrated an association between CYP2D6 phenotype and risk of P. vivax relapse with PQ therapy [44,51,52]. However, other studies have shown that factors such as transmission intensity and treatment adherence are better predictors of therapeutic failure with PQ than the CYP2D6 phenotype.
In vitro study on the effect of leonurine hydrochloride on the enzyme activity of cytochrome P450 enzymes in human liver microsomes
Published in Xenobiotica, 2021
Hui Zhao, Senyao Xue, Qingzhen Meng, Cui Zhou
CYP1A2 accounts for 13–15% of CYP, metabolizes approximately 4% of clinically used drugs and preferentially oxidizes aromatic hydrocarbons as well as heterocyclic and aromatic amines (Kato 2020). Although accounting for only 2% to 4% of all human liver CYP, CYP2D6 metabolizes about 30% of the marketed drugs, especially those that contain basic nitrogen and an aromatic ring with a hydrogen bond donor/acceptor (Bahar et al. 2017; Kato 2020), therefore much emphasis should be placed on its metabolism and potential for relevant drug interactions in the early process of drug discovery (Hicks et al. 2015). As the most abundant human hepatic CYP isoform, CYP3A4 is responsible for the metabolism of about 50% of known drugs (Hohmann et al. 2016). CYP3A4 can be inducible or inhibited by structurally diverse drugs and botanical compounds (Lolodi et al. 2017). So, the early identification of potential CYP1A2, CYP2D6, and CYP3A4 inhibitors is important to minimise the risk of relevant interactions. This study estimated the inhibitory effect on CYPs and found CYP1A2, CYP2D6, and CYP3A4 can be inhibited by LH at different degrees. These results can bring attention to possible LH-drug interactions on the level of CYP1A2, CYP2D6, and CYP3A4.