However, the variability of cyp2c9 intrinsic hepatic clearance clint,h,cyp2c9 among subjects of the same genotype has not. The first study was carried out using 10 healthy volunteers 6 extensive and 4 poor metabolizers. There is notable interindividual heterogeneity in drug response, affecting both drug ef. Download pdf human drug metabolism an introduction free. We found that cytochrome p450 cyp metabolism capacity and drug responsiveness of the primary human hepatocytes phhips. Interindividual variability in inhibition and induction of cytochrome. The most important enzyme system for drug metabolism is the cyp system. The coefficient of variation cv values for cyp3a4 content in human liver microsomes, hepatic blood flow, liver volume and body. Large interindividual variability has been observed in the metabolism of cyp2c19 substrates in vivo. Apart from changes in activity as a result of drug drug interactions by p450 induction or inhibition, the p450 enzymes can exhibit substantial interindividual variation in basal expression andor activity, leading to differences in the rates of drug elimination and response. Pharmacogenomic studies aim to elucidate the genetic bases for interindividual differences and to use. Age and sex have no apparent effect on the drugs metabolism and.
Apr 20, 2017 the activity of metabolic enzymes varies across individuals and populations. There are many reasons why the absorption, metabolism and excretion of drugs might vary. Probe drugs are metabolized by a single drug metabolizing enzyme and are administered to identify the function of that enzyme. Interindividual variability of cyp2c19catalyzed drug metabolism. Like any other drugs, antiallergic medications can be associated with large inter and intraindividual variability in their disposition. The cytochrome p450 p450 enzymes are the predominant enzyme system involved in human drug metabolism. Interdonor variability of phase iphase ii metabolism of three reference drugs in.
She and lauren zeise, 1 acting director of the california environmental protection agencys office of environmental health and hazard assessment, mentioned a number of recent studies highlighting important differences in how people respond to stressors. Likewise, variability in expression of microrna has been demonstrated to alter expression of p450s lamba et al. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy. There is a large interindividual variability in caffeine. Interindividual variability in cytochrome p450mediated drug metabolism article pdf available in drug metabolism and disposition. One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction.
Significant interindividual variability of exposure for cyp2c19 substrates may be only. Interindividual variability in human drug metabolism. Interindividual variability in acetaminophen glucuronidation. Interindividual variability of cyp2c19catalyzed drug metabolism due to differences in gene diplotypes and cytochrome p450 oxidoreductase content. Apr 21, 2016 these studies also uncovered a vast repertoire of genetic variants with profound impact on drug metabolism. However, the variability of cyp2c9 intrinsic hepatic clearance clint,h,cyp2c9 among subjects of the same genotype has not been reported. For characterization of the interindividual variability, microsomes were isolated from small intestinal samples of patients who had undergone resection for various reasons.
Atenolol was used as a negative and metoprolol as a positive control. Peter guengerich and paul b watkins and joseph c kolars and augustinus. Cytochrome p450 1a1, 2c9, 2c19, and 3a4 polymorphisms. Identifying sources of interindividual pharmacokinetic. Estimation of interindividual variability of pharmacokinetics.
Nuclear receptors and the regulation of drugmetabolizing. Interindividual variability in cytochrome p450mediated drug metabolism. Pdf interindividual variability of cyp2c19catalyzed drug. There is an up to 17fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of cyp enzymes accounts for a large part of this variation. Interindividual variability in human drug glucuronidation what we know and what we need to know laboratory of comparative and molecular pharmacogenomics department of pharmacology and experimental therapeutics. The aim of this study was to assess the ability of the cyp2d6 activity score as estimated from cyp2d6 genotype to predict cyp2d6 expression and enzyme activity. Dec 21, 2012 inhibitors of cyp3a4, such as fluconazole, and of cyp2d6, such as paroxetine, increase methadone blood concentrations. Interindividual variability in cytochrome p450mediated drug. Genetic factors that cause variability in human drug metabolism. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. Apapugt activities and enzyme kinetics were determined using hlms from 56 donors and. Interindividual variability was observed in nandrolone excretion patterns and kinetics, as well as for the noretiocholanolone. The human body can be parsed into a hierarchy of biological levels.
Interindividual variability in human drug glucuronidation. Inhibitors of cyp3a4, such as fluconazole, and of cyp2d6, such as paroxetine, increase methadone blood concentrations. The activity of metabolic enzymes varies across individuals and populations. Cyp2d6 genetic polymorphisms are considered a major contributor to the large interindividual variability in cyp2d6. In addition, inhibition by other drugs and dietary components contribute to the important interindividual variability in drug metabolism and utilisation. Cyp2d6 as explained 23% of the interindividual variability in cyp2d6 activity, but only 7. Interindividual variability of the clinical pharmacokinetics. Interindividual and intraindividual pharmacokinetic variability mark j. Jan 19, 2018 additionally, cyp2d6 enzyme activity, protein, and mrna levels were estimated. Prediction of interindividual variability in the pharmacokinetics of. Interindividual variability of metabolism is possibly affected. More generally, xenobiotic metabolism from the greek xenos stranger and biotic related to living beings is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organisms normal biochemistry, such as any drug. The book concludes with the role of drug metabolism in the commercial development of therapeutic agents as well as the pharmacology of some illicit drugs. These studies also uncovered a vast repertoire of genetic variants with profound impact on drug metabolism.
Interindividual differences in caffeine metabolism and. However, these genetic variants in p450s have not been fully investigated in cynomolgus macaques, a nonhuman primate species widely used in toxicological studies. Pdf interindividual variability in cytochrome p450. Interindividual variability in the cytochrome p450 3a4 drug. Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. Genetic and environmental factors causing variability in psychotropic drug response. Impact of drug treatment at neonatal ages on variability of. An important determinant of such interindividual differences in drug response is variability in the expression of drugmetabolizing enzymes andor. Prediction of interindividual differences in hepatic. The large interindividual variability in drug metabolism is one of the major reasons. Interindividual variability in acetaminophen apap glucuronidation may contribute to differences in susceptibility to apap intoxication in humans. Genetic and environmental causes for interindividual variability in.
Apart from changes in activity as a result of drug drug. Cyp2d6 is responsible for the metabolism of approximately 20% of clinically used medications and plays an important role in drug elimination. Interindividual variability in activity of the major drug metabolizing. Interindividual variation in hepatic drug metabolism the potential of.
Request pdf interindividual variability in activity of the major drug metabolizing enzymes in liver homogenates of 20 individuals background. Pdf interindividual variability in cytochrome p450mediated. Genetic basis of drug metabolism american journal of. The nicotine metabolism is an important determinant of the clearance of nicotine. Our findings suggest that intestinal disease and variability in intestinal cyp3a activity might be an unexamined variable that may contribute to interindividual variability in drug disposition. The study aimed to evaluate sources of this variability in cyp2c19 activity, focusing on. We rely on drug metabolism when we dose and would like to treat every individual the same way. The study aimed to evaluate sources of this variability in. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. High interindividual variability in plasma clopidogrel active. Impact of drug treatment at neonatal ages on variability. Interindividual pharmacokinetic and pharmacodynamic.
In a second study, the relative potency and duration of action of bopindolol were assessed in comparison to atenolol and slowrelease oxprenolol. Although less well studied, genetic variations in the noncoding region play an important role in the interindividual variation of human drug metabolism. Interindividual variability in human drug metabolism crc. High interindividual variability in plasma clopidogrel. Antiinflammatory agents, antituberculars, hydralazine, hypotensive agents, isoniazid, metabolism, pharmacogenetics, polymorphism, race, sulfonamides. Full text pdf 694k abstracts references85 a method for predicting the interindividual variability of human exposure for cyp3a4 substrates using monte carlo simulation was developed based on relevant factors. Apapugt activities and enzyme kinetics were determined using hlms from 56. Variation in the drug concentrations achieved by equivalent doses is a much more important cause of the inter individual variation in drug response encountered in clinical practice.
Pdf like any other drugs, antiallergic medications can be associated with large inter and intraindividual variability in their disposition. Interindividual variability of cyp2c19catalyzed drug. Given their complementary roles in drug disposition, it is not. Interindividual variability in cytochrome p450mediated. Oct 16, 2015 interindividual variability in cyp2d6mediated drug metabolism h. Path of a drug after administration by any route, a drug will reach the blood stream as schematically shown in f2. Individual variation in drug response pharmacology. Alterations in the expression andor activity of these enzymes result in changes in pharmacokinetics and consequently the pharmacodynamics of drugs that are metabolized by this set of enzymes. However, it remains uncertain whether human ipscderived hlcs can reproduce the interindividual difference in hepatic metabolism and drug response.
A few issues need to be considered to appraise the authors final conclusion that future utilization of their pharmacokinetic model may include prospective covariateadapted paclitaxel dosing to lower interindividual variability of drug exposure and toxicity. Developing and ageing as sources of variability in drug metabolism. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microrna that affect p450 expression, and ontogenic changes due to exposure to. University of chicago 2nd international workshop on clinical pharmacology of anticancer drugs madrid, spain. Metabolism of the immunosuppressant tacrolimus in the small. Interindividual pharmacokinetic and pharmacodynamic variabil. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human p450mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals. Drug metabolismtransport 566 j clin pharmacol 2007.
Body weight, sex, and the rate of drug metabolism are intrinsic physiological factors that can contribute to interindividual variability in the pharmacokinetic disposition of a drug martinez, court, fink. Cytochromes p450 p450s and their genetic variants in humans are important drugmetabolizing enzymes partly accounting for interindividual variations in drug metabolism and toxicity. Activity varies even among individuals sharing the same genotype. Thus, estimated clint,h variability can predict variability in the auc of drugs metabolized not only by. There is an up to 17fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of. Cyp2c19 is a member of the human drugmetabolizing family of cytochrome p450.
In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. Coxidation and glucuronidation miki nakajima, email protected tsuyoshi yokoi, drug metabolism and toxicology, division of pharmaceutical sciences, graduate school of medical science, kanazawa university, kanazawa, japan drug metabolism and toxicology, division of pharmaceutical sciences, graduate school of medical science. The benefits and risks of caffeine intake are summarized in table 1. Pdf interindividual variability of cyp2c19catalyzed. Hepatic drug metabolism influenced by genetic and environmental factors is a major source of variation in the response to a number of. The first study described here was carried out to define the role of a genetic determinant debrisoquine type oxidation polymorphism on plasma concentration of bopindolol and its. The amounts of nandrolone metabolites measured at the excretion peak varied between 1180 and 38 661. The purpose of this study was to identify the relevant udpglucuronosyltransferase ugt isoforms mediating apapugt activity in human liver microsomes hlms. The cyp2d6 protein level was found to be the major determinant of cyp2d6 activity, explaining 59% of variability.
Caffeine metabolism and pharmacokinetics caffeine metabolism and pharmacokinetics have been extensively studied in the past and revised recently arnaud, 2011. Review interindividual variability in nicotine metabolism. Interethnic differences in drug disposition and effects. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. Rare genetic variants in cellular transporters, metabolic. Nuclear receptors and variability in drug response drug metabolismtransport 567 the cell to the extracellular compartment. The terms in the table below are a collection of items from the lectures that you should be able to define and relate in a sentence or two to drug metabolism as set out in the notes. An important determinant of such interindividual differences in drug response is variability in the expression of drug.
Some complications of drug therapy that are due to variability in metabolism. In an in vitro model using pig small intestinal microsomes, 32 drugs were analyzed for their interactions with tacrolimus metabolism. Pdf gender and interindividual variability in pharmacokinetics. Interindividual differences in caffeine metabolism and factors driving caffeine consumption astrid nehlig inserm u 1129, pediatric neurology, neckerenfants malades hospital, university of paris descartes, inserm u1129, paris, france. Interindividual variability in nicotine metabolism. Notably, cyp2d6mediated drug metabolism exhibits large interindividual variability sachse et al. Interindividual variability in cyp2d6mediated drug metabolism h. Wires systems biology and medicine parsing interindividual drug variability figure 1 the rationale for a multiscale networkbased understanding of drug action. Metabolism of the immunosuppressant tacrolimus in the. Homework 1 drug metabolism 20 university of washington. The rate at which drugs and xenobiotics are metabolized by p450s affects the pharmacokinetics of the compound and, consequently, may also. Interindividual variability in inhibition and induction of. Results with a base model absorption rate interindividual variability was estimated at 1.
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