CYP2C19 polymorphisms account for inter-individual variability of drug metabolism in cynomolgus macaques

Inter-individual variability in the response to numerous drugs can be traced to a number of sources. One source of variability in drug response is the variability associated with the metabolic capacity of an individual. The component of metabolic capacity that will be the focus of this article is that determined by heredity. Pharmacogenetics is frequently referred to as the study of the effects of heredity on the disposition and response to medications. This article will review the pharmacokinetic and pharmacodynamic significance of pharmacogenetics as it pertains to a select number of cardiovascular agents. The enzyme systems responsible for drug metabolism discussed in this article will be limited to the P-450IID6 and N-acetylation pathways. Given the extensive use of cardiovascular agents in clinical practice that are affected by this genetic polymorphism, it is important for the practicing pharmacist to be aware of this phenomenon and its implications. Hopefully, the knowledge gained from this article will help practicing pharmacists to appreciate the clinical significance of polymorphic drug metabolism and provide a basis for the application of this knowledge to a variety of practice settings.

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Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

Genes ◽

10.3390/genes11121509 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1509

Author(s):

Laura M. de Jong ◽

Wim Jiskoot ◽

Jesse J. Swen ◽

Martijn L. Manson

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Drug Response ◽

Genetic Factors ◽

Potential Role ◽

In Vitro Models ◽

Experimental Models ◽

Individual Variability ◽

The Individual

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

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GENETIC CONTROL OF DRUG LEVELS AND OF THE INDUCTION OF DRUG-METABOLIZING ENZYMES IN MAN: INDIVIDUAL VARIABILITY IN THE EXTENT OF ALLOPURINOL AND NORTRIPTYLINE INHIBITION OF DRUG METABOLISM

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1971.tb46950.x ◽

1971 ◽

Vol 179 (1 Drug Metaboli) ◽

pp. 752-772 ◽

Cited By ~ 46

Author(s):

Elliot S. Vesell ◽

G. Thomas Passananti ◽

Frank E. Greene ◽

John G. Page

Keyword(s):

Drug Metabolism ◽

Genetic Control ◽

Individual Variability ◽

Drug Metabolizing Enzymes ◽

Metabolizing Enzymes ◽

Drug Levels

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Cytochrome P450 1A1, 2C9, 2C19, and 3A4 Polymorphisms Account for Interindividual Variability of Toxicological Drug Metabolism in Cynomolgus Macaques

Chemical Research in Toxicology ◽

10.1021/acs.chemrestox.8b00257 ◽

2018 ◽

Vol 31 (12) ◽

pp. 1373-1381 ◽

Cited By ~ 3

Author(s):

Yasuhiro Uno ◽

Shotaro Uehara ◽

Norie Murayama ◽

Hiroshi Yamazaki

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Interindividual Variability ◽

Cytochrome P450 1A1 ◽

Cynomolgus Macaques

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Inter-individual variation shapes the human microbiome

Behavioral and Brain Sciences ◽

10.1017/s0140525x1800287x ◽

2019 ◽

Vol 42 ◽

Author(s):

Emily F. Wissel ◽

Leigh K. Smith

Keyword(s):

Individual Differences ◽

Individual Variation ◽

Human Microbiome ◽

Individual Variability ◽

Microbiota Composition ◽

Target Article ◽

Microbiome Research

Abstract The target article suggests inter-individual variability is a weakness of microbiota-gut-brain (MGB) research, but we discuss why it is actually a strength. We comment on how accounting for individual differences can help researchers systematically understand the observed variance in microbiota composition, interpret null findings, and potentially improve the efficacy of therapeutic treatments in future clinical microbiome research.

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EURRECAs Approach for Estimating Micronutrient Requirements

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000071 ◽

2011 ◽

Vol 81 (4) ◽

pp. 256-263 ◽

Cited By ~ 22

Author(s):

Christophe Matthys ◽

Pieter van ‘t Veer ◽

Lisette de Groot ◽

Lee Hooper ◽

Adriënne E.J.M. Cavelaars ◽

...

Keyword(s):

Reference Values ◽

Policy Decision ◽

Individual Variability ◽

The Body ◽

Decision Makers ◽

Nutrient Requirements ◽

Factorial Approach ◽

Dietary Reference Values ◽

Health Policy Decision ◽

Quantitative Integration

In Europe, micronutrient dietary reference values have been established by (inter)national committees of experts and are used by public health policy decision-makers to monitor and assess the adequacy of diets within population groups. The approaches used to derive dietary reference values (including average requirements) vary considerably across countries, and so far no evidence-based reason has been identified for this variation. Nutrient requirements are traditionally based on the minimum amount of a nutrient needed by an individual to avoid deficiency, and is defined by the bodys physiological needs. Alternatively the requirement can be defined as the intake at which health is optimal, including the prevention of chronic diet-related diseases. Both approaches are confronted with many challenges (e. g., bioavailability, inter and intra-individual variability). EURRECA has derived a transparent approach for the quantitative integration of evidence on Intake-Status-Health associations and/or Factorial approach (including bioavailability) estimates. To facilitate the derivation of dietary reference values, EURopean micronutrient RECommendations Aligned (EURRECA) is developing a process flow chart to guide nutrient requirement-setting bodies through the process of setting dietary reference values, which aims to facilitate the scientific alignment of deriving these values.

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