Metabolism of the immunosuppressant tacrolimus in the small. 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. There is notable interindividual heterogeneity in drug response, affecting both drug ef. Interindividual variation in hepatic drug metabolism the potential of. 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. Pdf interindividual variability of cyp2c19catalyzed drug. An important determinant of such interindividual differences in drug response is variability in the expression of drugmetabolizing enzymes andor. Interindividual variability of cyp2c19catalyzed drug metabolism. One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction. Impact of drug treatment at neonatal ages on variability. There is an up to 17fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of.
Antiinflammatory agents, antituberculars, hydralazine, hypotensive agents, isoniazid, metabolism, pharmacogenetics, polymorphism, race, sulfonamides. 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. Interindividual variability in acetaminophen apap glucuronidation may contribute to differences in susceptibility to apap intoxication in humans. There is a large interindividual variability in caffeine. The coefficient of variation cv values for cyp3a4 content in human liver microsomes, hepatic blood flow, liver volume and body. 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. Interindividual and intraindividual pharmacokinetic variability mark j. Download pdf human drug metabolism an introduction free. Metabolism of the immunosuppressant tacrolimus in the.
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. Nuclear receptors and variability in drug response drug metabolismtransport 567 the cell to the extracellular compartment. Interindividual variability of metabolism is possibly affected. Identifying sources of interindividual pharmacokinetic. Pdf gender and interindividual variability in pharmacokinetics. Jan 19, 2018 additionally, cyp2d6 enzyme activity, protein, and mrna levels were estimated. Interindividual variability in cytochrome p450mediated drug. Interindividual variability of cyp2c19catalyzed drug metabolism due to differences in gene diplotypes and cytochrome p450 oxidoreductase content. 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. Request pdf interindividual variability in activity of the major drug metabolizing enzymes in liver homogenates of 20 individuals background.
Rare genetic variants in cellular transporters, metabolic. Notably, cyp2d6mediated drug metabolism exhibits large interindividual variability sachse et al. Nuclear receptors and the regulation of drugmetabolizing. 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. Interethnic differences in drug disposition and effects. 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. Interindividual and intraindividual pharmacokinetic. The nicotine metabolism is an important determinant of the clearance of nicotine. Given their complementary roles in drug disposition, it is not.
Apr 21, 2016 these studies also uncovered a vast repertoire of genetic variants with profound impact on drug metabolism. Pdf interindividual variability of cyp2c19catalyzed. Apr 20, 2017 the activity of metabolic enzymes varies across individuals and populations. Interindividual variability in the cytochrome p450 3a4 drug. 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. Apapugt activities and enzyme kinetics were determined using hlms from 56 donors and. High interindividual variability in plasma clopidogrel active. Cyp2d6 genetic polymorphisms are considered a major contributor to the large interindividual variability in cyp2d6. Genetic basis of drug metabolism american journal of. Significant interindividual variability of exposure for cyp2c19 substrates may be only. The benefits and risks of caffeine intake are summarized in table 1. Interdonor variability of phase iphase ii metabolism of three reference drugs in.
Like any other drugs, antiallergic medications can be associated with large inter and intraindividual variability in their disposition. Cyp2c19 is a member of the human drugmetabolizing family of cytochrome p450. Apart from changes in activity as a result of drug drug. Thus, estimated clint,h variability can predict variability in the auc of drugs metabolized not only by. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. Pharmacogenomic studies aim to elucidate the genetic bases for interindividual differences and to use. Cyp2d6 as explained 23% of the interindividual variability in cyp2d6 activity, but only 7. Interindividual variability in cytochrome p450mediated. The rate at which drugs and xenobiotics are metabolized by p450s affects the pharmacokinetics of the compound and, consequently, may also.
We found that cytochrome p450 cyp metabolism capacity and drug responsiveness of the primary human hepatocytes phhips. Path of a drug after administration by any route, a drug will reach the blood stream as schematically shown in f2. Caffeine metabolism and pharmacokinetics caffeine metabolism and pharmacokinetics have been extensively studied in the past and revised recently arnaud, 2011. 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. Activity varies even among individuals sharing the same genotype. However, the variability of cyp2c9 intrinsic hepatic clearance clint,h,cyp2c9 among subjects of the same genotype has not. However, the variability of cyp2c9 intrinsic hepatic clearance clint,h,cyp2c9 among subjects of the same genotype has not been reported. 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 cyp2d6 protein level was found to be the major determinant of cyp2d6 activity, explaining 59% of variability. These studies also uncovered a vast repertoire of genetic variants with profound impact on drug metabolism.
The human body can be parsed into a hierarchy of biological levels. The purpose of this study was to identify the relevant udpglucuronosyltransferase ugt isoforms mediating apapugt activity in human liver microsomes hlms. Interindividual variability in inhibition and induction of. P450 drug metabolism i 20 university of washington. Interindividual variability in human drug metabolism crc. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. Interindividual variability in inhibition and induction of cytochrome. N l benowitz, p jacob, r t jones and j rosenberg journal of pharmacology and experimental therapeutics may 1, 1982, 221 2 368372. Cytochrome p450 1a1, 2c9, 2c19, and 3a4 polymorphisms. Review interindividual variability in nicotine metabolism. Results with a base model absorption rate interindividual variability was estimated at 1. Interindividual variability of the clinical pharmacokinetics.
Interindividual variability in cytochrome p450mediated drug metabolism article pdf available in drug metabolism and disposition. Genetic and environmental factors causing variability in psychotropic drug response. Interindividual pharmacokinetic and pharmacodynamic. Wires systems biology and medicine parsing interindividual drug variability figure 1 the rationale for a multiscale networkbased understanding of drug action. Interindividual variability in activity of the major drug metabolizing. Gender and interindividual variability in pharmacokinetics. Erratic or unpredictable response to drugs remains a challenge of modern drug therapy.
Estimation of interindividual variability of pharmacokinetics. The large interindividual variability in drug metabolism is one of the major reasons. Genetic and environmental causes for interindividual variability in. An important determinant of such interindividual differences in drug response is variability in the expression of drug.
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 cytochrome p450 p450 enzymes are the predominant enzyme system involved in human drug metabolism. Developing and ageing as sources of variability in drug metabolism. Genetic polymorphisms in cyp2c9 cause significant interindividual variability in the metabolism of its substrates. Prediction of interindividual differences in hepatic. 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. Pdf interindividual variability in cytochrome p450. Interindividual variability in activity of the major drug metabolizing enzymes in.
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. The amounts of nandrolone metabolites measured at the excretion peak varied between 1180 and 38 661. Although less well studied, genetic variations in the noncoding region play an important role in the interindividual variation of human drug metabolism. Drug metabolismtransport 566 j clin pharmacol 2007. Probe drugs are metabolized by a single drug metabolizing enzyme and are administered to identify the function of that enzyme.
In addition, inhibition by other drugs and dietary components contribute to the important interindividual variability in drug metabolism and utilisation. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Inhibitors of cyp3a4, such as fluconazole, and of cyp2d6, such as paroxetine, increase methadone blood concentrations. 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. In a second study, the relative potency and duration of action of bopindolol were assessed in comparison to atenolol and slowrelease oxprenolol. Interindividual variability of cyp2c19catalyzed drug.
Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. The activity of metabolic enzymes varies across individuals and populations. Likewise, variability in expression of microrna has been demonstrated to alter expression of p450s lamba et al. The study aimed to evaluate sources of this variability in. Interindividual differences in caffeine metabolism and. Peter guengerich and paul b watkins and joseph c kolars and augustinus. Genetic factors that cause variability in human drug metabolism. Interindividual pharmacokinetic and pharmacodynamic variabil. Some complications of drug therapy that are due to variability in metabolism. There are many reasons why the absorption, metabolism and excretion of drugs might vary.
Oct 16, 2015 interindividual variability in cyp2d6mediated drug metabolism h. Interindividual variability in acetaminophen glucuronidation. However, these genetic variants in p450s have not been fully investigated in cynomolgus macaques, a nonhuman primate species widely used in toxicological studies. The study aimed to evaluate sources of this variability in cyp2c19 activity, focusing on. Interindividual variability in human drug glucuronidation. The first study was carried out using 10 healthy volunteers 6 extensive and 4 poor metabolizers. Atenolol was used as a negative and metoprolol as a positive control. Homework 1 drug metabolism 20 university of washington. Interindividual variability was observed in nandrolone excretion patterns and kinetics, as well as for the noretiocholanolone. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. High interindividual variability in plasma clopidogrel. Individual variation in drug response pharmacology. Cytochromes p450 p450s and their genetic variants in humans are important drugmetabolizing enzymes partly accounting for interindividual variations in drug metabolism and toxicity. 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.
Interindividual variability in nicotine metabolism. Large interindividual variability has been observed in the metabolism of cyp2c19 substrates in vivo. Interindividual variability in the metabolism of cardiovascular drugs. 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. In an in vitro model using pig small intestinal microsomes, 32 drugs were analyzed for their interactions with tacrolimus metabolism. Pdf interindividual variability in cytochrome p450mediated. Pdf like any other drugs, antiallergic medications can be associated with large inter and intraindividual variability in their disposition. Prediction of interindividual variability in the pharmacokinetics of. Interindividual variability in human drug metabolism. Apapugt activities and enzyme kinetics were determined using hlms from 56.
Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. 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. Impact of drug treatment at neonatal ages on variability of. However, it remains uncertain whether human ipscderived hlcs can reproduce the interindividual difference in hepatic metabolism and drug response. Interindividual variability in cytochrome p450mediated drug metabolism. Dec 21, 2012 inhibitors of cyp3a4, such as fluconazole, and of cyp2d6, such as paroxetine, increase methadone blood concentrations. Cyp2d6 is responsible for the metabolism of approximately 20% of clinically used medications and plays an important role in drug elimination.
University of chicago 2nd international workshop on clinical pharmacology of anticancer drugs madrid, spain. Interindividual variability in cyp2d6mediated drug metabolism h. The most important enzyme system for drug metabolism is the cyp system. 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.
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