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