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Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The efficacy of a drug (as well as its toxicity) depends among others on the cytochrome P450 mediated drug metabolism (oxidative drug metabolizing enzymes; see also other chapters in Pharmaceutical Biocatalysis volumes). Of the more than 50 CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90% of drugs, and of these P450 2D6 is responsible for the metabolism of almost 25% of drugs among them different types of analgesics, anti-arrhythmic agents, antidepressant and β-blockers. The response to standard doses of a drug may be different from patient to patient due to the fact that CYP 450 enzymes exhibit genetic variability (polymorphism). Those with two copies of wild-type genetic alleles are normal so-called “extensive” metabolizers whereas persons with two copies of variant alleles are “poor” metabolizers, and those with one variant and one wild-type allele show reduced enzyme activity (Lynch and Price, 2007). Flockhart (2007) provided a table with lists of drugs in columns under the designation of specific cytochrome P450 isoforms with published evidence (see cited literature) that the respective drug is metabolized, at least in part, via that isoform. In 2007 the FDA approved the first genotype test (Roche AmpliChip cytochrome P450 genotyping test) a DNA microarray that enables the detection of 29 polymorphisms of CYP2D6 and two of CYP2C19 from a blood sample. Investigations into cytochrome P450 2D6 genotype assessment and phenotype prediction using the Roche test have been reported by Rebsamen et al. (2009).
Pharmacological treatment of bipolar affective disorder in old age
Published in Stephen Curran, John P Wattis, Practical Management of Affective Disorders in Older People, 2018
Risperidone is a benzisoxazole derivative with high affinity for serotonin, dopamine and alpha 1 and 2 adrenergic receptors. Oral risperidone is rapidly absorbed, reaching maximum plasma concentration after one to two hours. It is largely hydroxylated by the cytochrome P450 2D6 enzyme. The elimination half-life is about 20 hours. Excretion is mostly through the urine. Clearance is reduced in elderly people and in those with renal impairment.
Towards precision medicine
Published in Yann Joly, Bartha Maria Knoppers, Routledge Handbook of Medical Law and Ethics, 2014
For instance, cytochrome P450 2D6 (CYP2D6) plays a role in metabolizing 25 per cent of current drugs and has been associated with the occurrence of Risperidone ADRs (Jose de Leon et al. 2005). Poor metabolizers lack this enzyme (including 7 per cent of the Caucasian population) and high metabolizers bear two copies of the CYP2D6 gene (including 2 per cent of Northern Europeans, 10 per cent of Southern Europeans and 30 per cent of the African population) (Pirmohamed and Hughes 2013; Bradford 2002).
Personalizing tamoxifen therapy in adjuvant therapy: a brief summary of the ongoing discussion
Published in Expert Review of Clinical Pharmacology, 2023
Anabel Sanchez-Spitman, Henk-Jan Guchelaar
In this complex metabolic pathway, the Cytochrome P450 2D6 (CYP2D6) enzyme in the liver has frequently been reported as the limiting factor of tamoxifen metabolism [12]. The CYP2D6 is a highly polymorphic gene for which more than 100 polymorphisms have been described [13]. These variants can encode for an CYP2D6 enzyme that is nonfunctional, fully functional or has decreased activity. According to the combination of the CYP2D6 alleles, individuals can classically be classified into four CYP2D6 phenotypes: poor metabolizer (PM), intermediated metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM). Another manner to categorize patients is the CYP2D6 gene activity score [14] in which a score of 2 represents a fully functional enzyme, whereas a score of 0 represents a non-active CYP2D6 enzyme.
An alternative start regimen with aripiprazole once-monthly in patients with schizophrenia: population pharmacokinetic analysis of a single-day, two-injection start with gluteal and/or deltoid intramuscular injection
Published in Current Medical Research and Opinion, 2021
Yanlin Wang, Xiaofeng Wang, Matt Harlin, Frank Larsen, Moeen Panni, Murat Yildirim, Jessica Madera, Liz Arias, Andy Forbes, Nihal Mustafa, Inez Ruiz-White, Arash Raoufinia
The population mean of each PK parameter was fixed to the value estimated in the previously developed model for oral and gluteal administration, except for DKa, which was estimated using data following deltoid administration. The interindividual variability for Ka was fixed to the value estimated in the previously developed model, while that for clearance (CL), central volume of distribution (Vc), and the 1st-order absorption rate constants following IM injections were estimated (DKa) or re-estimated (IMKa) using the final combined analysis data set. The previous model also included the following covariate effects: (i) the effect of cytochrome P450 2D6 (CYP2D6) metabolism status (extensive [EM; also known as “normal metabolizer”] vs poor metabolizer [PM]) on CL, (ii) the effects of co-administration of strong inhibitors of CYP2D6 or CYP3A4 on CL, and (iii) the effects of gender and body mass index on IMKa. Parameter estimation for the previously developed model is presented in Table 1. It was assumed that the covariate effect remained the same as for the previously developed model, and that the gender and body mass index effects on IMKa, estimated from data following IM injection mainly in the gluteus maximus, were also present for the deltoid injection. No further structural change or covariate analysis was conducted. The goodness of fit of the final combined model was assessed by standard diagnostic plots (observed vs population prediction [PRED], observed vs individual prediction, conditional weighted residual error [CWRES] vs PRED, and CWRES vs time).
Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Nawaf A. Alsaif, Mohammed S. Taghour, Mohammed M. Alanazi, Ahmad J. Obaidullah, Abdulrahman A. Al-Mehizia, Manal M. Alanazi, Saleh Aldawas, Alaa Elwan, Hazem Elkady
To investigate pharmacokinetics properties of the prepared compounds, computer aided ADME studies were accomplished using Accelrys Discovery Studio 4.0 software. Sorafenib was used as a reference molecule. These studies include the estimation of certain parameters. 1) Blood brain barrier penetration which measures the ability of molecule to diffuse through blood brain barrier. 2) Absorption level which determines human intestinal absorption (HIA) of a chemical after its oral administration. A well-absorbed compound is one that is absorbed at least 90% into the blood stream59,60. iii) Solubility level in which the solubility of a chemical in water was predicted at 25 °C. iv) CYP2D6 binding which analyzes cytochrome P450 2D6 enzyme inhibition61,62. v) Plasma protein binding which predicts the fraction of drug bound to plasma proteins in the blood63. The results were predicted and listed in Table 6.