The route of administration, the pharmacokinetics of the drug, conversion to toxic metabolites, and interindividual responsiveness are just a few factors. Cyp2c8 is a major drug metabolizing enzyme known to be involved in the metabolism of over 100 drugs. Thus, the interindividual variability of the auc of cyp3a4 substrates was predictable for both intravenous and oral administration. The objective of this monograph is to evaluate the current status of knowledge of metabolism, pharmacokinetics, and pharmacodynamics of drugs of abuse. Interindividual variability in acetaminophen sulfation by human fetal liver. Interindividual and regional variability in drug transporter. Interindividual variability in human drug metabolism crc. The identification of ces1 and ces2 and their variability in human. For instance, genetic factors, different physical characteristics, the presence of diseasesdisorders, and multiple drug interactions may be sources of interindividual variability. Interindividual variability of soil arsenic metabolism by human gut microbiota using shime model article pdf available in chemosphere 184 june 2017 with 597 reads how we measure reads. Prediction of interindividual differences in hepatic.
One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction. Finally, the ontogeny of drugmetabolizing enzymes has been. Indeed, variability in the responsiveness of all living organisms to toxic chemicals has general importance in biology. We investigated its gene and protein expression as well as interindividual variations in aadac activities in a large number of human lungs n 25 using. There is notable interindividual heterogeneity in drug response, affecting. Cyp2d6 genetic polymorphisms are considered a major contributor to the large interindividual variability in cyp2d6. Assessing the propagation of genetic variability in drug metabolism to pharmacokinetics and pharmacodynamics gemma l. Estimation of interindividual variability of pharmacokinetics. 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 human drug glucuronidation. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. To date, the presence and activity of the aadac enzyme in human lungs has been scarcely examined. Glucuronidation of drugs represents a major pathway of human drug metabolism.
Role of phenotyping and genotyping in the measurement of. Human ugt1a4 and ugt1a3 conjugate 25hydroxyvitamin d3. Among the causes of variability in human drug response, interindividual variation in enzymes, receptors and transporters play an important role. Likewise, variability in expression of microrna has been demonstrated to alter expression of p450s lamba et al. Temellini department of experimental biomedicine, medical school, university of pisa, italy. Apr 20, 2017 the activity of metabolic enzymes varies across individuals and populations. P450 drug metabolism i 20 university of washington. Nuclear receptors and variability in drug response drug metabolismtransport 567 the cell to the extracellular compartment. Pdf interindividual variability of soil arsenic metabolism. 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. Path of a drug after administration by any route, a drug will reach the blood stream as. Human arylacetamide deacetylase aadac is a single microsomal serine esterase involved in the hydrolysis of many acetylcontaining drugs. Prediction of interindividual variability in the pharmacokinetics of. Gluc would release the parent compound, thereby modifying drug disposition.
Interindividual variations in immunoreactivity and function of three major human drug metabolising p450 monooxygenases has been investigated in liver microsomes from 42 caucasians kidney donors or liver biopsies methods. P450 enzymes are the predominant enzyme system involved in human drug metabolism. Hostrelated factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans torsten bohn1, charles desmarchelier2, lars o. In all cases, the simulated mean and sd values reflected the reported values.
There are many factors that contribute to our inability to quantitatively predict drug interactions. Jan 19, 2018 the cyp2d6 gene region was sequenced in 115 healthy human liver tissue samples to determine their cyp2d6 as. However, the variability of cyp2c9 intrinsic hepatic clearance clint,h,cyp2c9 among subjects of the. Published studies that analyzed variability in the expression of dmet genes were limited by sample sizes and the number of genes profiled.
Jan 23, 2019 the interindividual variability in transporter abundance percentage of coefficient of variation %cv was 3557% ba17 and 2746% ba39. Significant interindividual variability of exposure for cyp2c19 substrates may be only partly due to genetic polymorphism. Nuclear receptors and the regulation of drugmetabolizing. There is a large interindividual variability in caffeine consumption and in its effects on the human body. Cyp2d6 is responsible for the metabolism of approximately 20% of clinically used medications and plays an important role in drug elimination. 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. Birth defects research part a clinical and molecular teratology, 82 3, 155165. Cytochrome p450 1a1, 2c9, 2c19, and 3a4 polymorphisms. Pdf interindividual variability in cytochrome p450.
Activity varies even among individuals sharing the same genotype. The purpose of this study was to identify the relevant udpglucuronosyltransferase ugt isoforms mediating apapugt activity in human liver microsomes hlms. Interindividual variability in the expression of drugmetabolizing enzymes and transporters dmets in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Interindividual variability in nicotine metabolism. Cytochromes p450 p450s and their genetic variants in humans are important drugmetabolizing enzymes partly accounting for interindividual variations in drug metabolism and toxicity. Developing and ageing as sources of variability in drug metabolism. However, it remains uncertain whether human ipscderived hlcs can reproduce the interindividual difference in hepatic metabolism and drug response. Interindividual variability in the glucuronidation and. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. However, the hype following completion of the human genome project of a. 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.
Interindividual differences in caffeine metabolism and. Genetic and environmental causes for interindividual variability in. 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. Interindividual variability in levels of human microsomal. The activity of metabolic enzymes varies across individuals and populations. The study aimed to evaluate sources of this variability in. Interindividual variations in immunoreactivity and function of three major human drug metabolising p450 monooxygenases has been investigated in liver microsomes from 42 caucasians kidney donors or liver biopsies. Interindividual variability in the glucuronidation and sulphation of ethinyloestradiol in human liver.
N l benowitz, p jacob, r t jones and j rosenberg journal of pharmacology and experimental therapeutics may 1, 1982, 221 2 368372. In both cases, cleavage of the glucuronide by human. Various stages of drug discovery are illustrated in f1. 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. These findings raise the possibility that interindividual differences in the efficiency of 25ohd 3 glucuronidation by ugt1a4 might contribute to variability in the efficiency of intestinal calcium absorption and cyp3a4dependent drug metabolism. Interindividual variability in cyp2d6mediated drug metabolism h. Numerous studies show that the glucuronides formed can accumulate during chronic therapy andor have direct pharmacological activity. Interindividual variability in acetaminophen apap glucuronidation may contribute to differences in susceptibility to apap intoxication in humans. Sinzcharacterization of phase i and phase ii hepatic drug metabolism activities in a panel of human.
Indeed, the interindividual variability in cyp3a4 drugmetabolizing activity has been estimated to be between 5 and 20fold. 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. Interindividual variability in human drug metabolism. Oct 16, 2015 interindividual variability in cyp2d6mediated drug metabolism h. Apapugt activities and enzyme kinetics were determined. Interethnic differences in drug disposition and effects.
Thummel and evan d kharasch, journal drug metabolism and disposition. Interindividual variability an overview sciencedirect topics. The nicotine metabolism is an important determinant of the clearance of nicotine. These results establish that human alfentanil metabolism is catalyzed predominantly, if not exclusively, by p450 3a34. 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. Fentanyl metabolism by human hepatic and intestinal. Alterations in the expression andor activity of these enzymes result in changes in pharmacokinetics and consequently the pharmacodynamics of drugs that are metabolized by. Interindividual variability in cytochrome p450mediated. A study of inter individual variability in the phase ii metabolism of xenobiotics in human skin. However, these genetic variants in p450s have not been fully investigated in cynomolgus macaques, a nonhuman primate species widely used in toxicological studies. 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 cytochrome p450mediated drug metabolism.
Apapugt activities and enzyme kinetics were determined using hlms from 56 donors and. Interindividual variability in the expression of drugmetabolizing enzymes and transporters dmets in human liver may contribute to. Pk basis, where knowledge of drug metabolizing enzymes dmes and. It is a clinically important enzyme that plays a critical role in the metabolism and related drugdrug interactions of a variety of therapeutic agents, including proton pump inhibitors, antiepileptic agents, antiplatelet drugs and antidepressants. After incubation with human, rat, and pig small intestinal microsomes, the metabolites odemethyl and,15odemethyl tacrolimus were identified.
Interindividual variation in hepatic drug metabolism the potential of. Individual differences in the response of people to a drug and variability in the response that occurs when patients are given a drug on several occasions are important problems in clinical pharmacology. These findings suggest that interindividual differences in drug metabolism capacity and drug response could be predicted by using hlcs differentiated from human ips cells. Implications for pharmacogenetic investigations of druginduced birth defects. Interindividual variability of soil arsenic metabolism by. The cytochrome p450 p450 enzymes are the predominant enzyme system involved in human drug metabolism. Interindividual variability in inhibition and induction of. Interindividual variability in the metabolism of cardiovascular drugs. A study of interindividual variability in the phase ii.
The coefficient of variation cv values for cyp3a4 content in human liver microsomes, hepatic blood flow, liver volume and body. For characterization of the interindividual variability, microsomes were isolated from small intestinal samples of patients who had undergone resection for various reasons. Interindividual differences in caffeine metabolism and factors driving caffeine consumption. Dickinson university of sheffield, school of pharmacy and pharmaceutical sciences, 3. Pharmacokinetics, metabolism, and pharmaceutics of drugs. Genetic and environmental factors causing variability in psychotropic drug response. Peter guengerich and paul b watkins and joseph c kolars and augustinus. There are many reasons why the absorption, metabolism and excretion of drugs might vary. Genetic factors that cause variability in human drug metabolism. We investigated its gene and protein expression as well as interindividual variations in aadac activities in a large. We believe that ipshlcs would be a powerful technology not only for accurate and efficient drug development, but also for personalized drug therapy.
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, the variability of cyp2c9 intrinsic hepatic clearance clint,h,cyp2c9 among subjects of the same genotype has not been reported. Pk individualization is a major challenge in pk modeling because the causes of variability are usually partially unknown. Genetic polymorphisms in cyp2c9 cause significant interindividual variability in the metabolism of its substrates.
Pdf lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Interindividual variability in acetaminophen sulfation by. Interindividual variability an overview sciencedirect. Pdf cyp2d6 protein level is the major contributor to inter. Additionally, cyp2d6 enzyme activity, protein, and mrna levels were estimated. We also successfully predicted the clearance of midazolam in japanese and in european american subjects. Best known are the interindividual differences in drug metabolism, caused by geneticenvironmental interactions, especially for those drugs mainly metabolised by genetically polymorphic enzymes. Although both triazolam and alprazolam are anxiolytic agents that are predominantly metabolized by cyp3a4, the human pharmacokinetics of the two drugs differ. Interindividual variability in expression and activity of. Recently, advances in the understanding of the interindividual variability in. Peasexenobiotic metabolism in human skin and 3d human skin reconstructs.
Thummel and evan d kharasch, journaldrug metabolism and disposition. Understanding of pharmacokinetic and metabolism characteristics of the selected compounds is needed in designing appropriate human clinical trials. The interindividual variability in transporter abundance percentage of coefficient of variation %cv was 3557% ba17 and 2746% ba39. Interindividual variability in catalytic activity and. The study aimed to evaluate sources of this variability in cyp2c19 activity, focusing on. Cyp2d6 as explained 23% of the interindividual variability in cyp2d6 activity, but only 7. For instance, genetic factors, different physical characteristics, the presence of diseasesdisorders, and multiple drug interactions may be. 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. Drug metabolismtransport 566 j clin pharmacol 2007. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. Notably, cyp2d6mediated drug metabolism exhibits large interindividual variability sachse et al. Human interindividual variability in its in vitro hepatic biotransformation and the identification of the cytochrome p450 isoforms involved, chemicobiological interactions on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Human alfentanil metabolism by cytochrome p450 3a34.
Cyp2d6 protein level is the major contributor to interindividual variability in cyp2d6mediated drug metabolism in healthy human liver tissue. Interindividual variability of cyp2c19catalyzed drug metabolism. We found that cytochrome p450 cyp metabolism capacity and drug responsiveness of the primary human hepatocytes phhips. Interindividual variability in cytochrome p450mediated drug metabolism article pdf available in drug metabolism and disposition. 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. Interindividual variability of cyp2c19catalyzed drug. Interindividual variability in acetaminophen glucuronidation.
Inter individual variability in pharmacokinetics can lead to unexpected side effects and treatment failure, and is therefore an important factor in drug development. Individual variation in drug response pharmacology. The metabolism of tacrolimus by human small intestine was inhibited by anticyp3a, troleandomycin, and erythromycin. Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. Cyp2c19 is a member of the human drugmetabolizing family of cytochrome p450. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. Part 1 of the article covers the basics of drug metabolism. Gene expression variability in human hepatic drug metabolizing. An important determinant of such interindividual differences in drug response is variability in the expression of drugmetabolizing enzymes andor. Pdf interindividual variability in cytochrome p450mediated. Metabolism of the immunosuppressant tacrolimus in the. Interindividual variability in cytochrome p450mediated drug. Interindividual variability in human alfentanil disposition and alfentanil drug interactions may be attributable to individual differences in p450 3a34 activity. An important determinant of such interindividual differences in drug response is variability in the expression of drug.
1007 930 36 108 1182 1443 614 489 1173 554 225 802 1352 226 1206 669 327 703 1186 1328 385 707 1371 313 159 659 727 801 1086 1129 600 185 267 1362 1471 416 405 706 215 826 1327 4 716