In vitro and in vivo small intestinal metabolism of cyp3a and ugt substrates in preclinical animals species and humans. Hepatic cyp form induction in humans may lead to clinically important drugdrug interactions. Safety testing of drug metabolites guidance for industry. Drug metabolism in animals may be drastically different from that in humans hence the need for clinical trials ii. Absorption, distribution, metabolism, and elimination. Thus, some major species differences in drug metabolism68,69 may tentatively be rationalized by species specific requirements. Pdf species differences between mouse, rat, dog, monkey. Pdf animal models are commonly used in the preclinical development of new drugs to predict the. Strategies for in vitro metabolic stability testing. 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. Differences among species in rates of aging are believed to be attributable to differences in metabolic rates and associated cumulative oxidative injury.
Species differences in nglucuronidation drug metabolism. The important equations are highlighted and the commonly used terms in pkpddm are summarized in a glossary at the end of the book. During its evolution, every animal species was under an individual selection pressure with regard to drug metabolism, in major part dictated by its preferred diet. Occurs in the smooth endoplasmic reticulum ser of the liver cells 2. Species differences in drug metabolism dr ted williams. I hope that all those who consult this book find it useful as an easytounderstand. Species differences in the oxidative desulfurization of a. Species differences in the disposition and metabolism of. Molecular mechanisms for species differences in organic anion.
Small animal clinical pharmacology and therapeutics. One of the fundamental challenges drug metabolism scientists face in drug discovery and development is the extrapolation of metabolic data and risk assessment from animals to humans. The importance of cytochrome p450 isoforms to species differences in the metabolism of foreign compounds and activation of procarcinogens has been identified. Pdf species differences between mouse, rat, dog, monkey and. Species differences in the induction of drug metabolism by rifampicin. This body of research identified differences in the cyp transcriptome and cyp substrate depletion profile between the two species that suggests the need for species specific. Contains hepatic drugmetabolising enzymes cytochrome p450 referred to as cyp 1, 2. Brain concentrations and braintoplasma ratios were compared. Nonmicrosomal enzymes drug metabolism aldehyde free.
A study of na by the national toxicology program indicated that chronic administration in the diet at doses equivalent to 82 and 175 mgkgday for rats, and 175 and 475 mgkgday for mice resulted in neoplastic lesions in the preputial and clitoral glands of male and female fischer 344 rats. Nalidixic acid na is an antimicrobial drug that has been used to treat urinary tract infections. Much work is still needed to better understand the molecular causes of drug metabolism and disposition differences in cats, thereby enabling more rational prescribing of existing medications, and. Humanized ugt2 and cyp3a transchromosomic rats for. These are due largely to alterations in isoform composition, regulation, expression, and catalytic activities of drug. In this study, the stereoselective pharmacokinetics of hsg4112 were investigated in rats and dogs, and the underlying mechanism was investigated. This body of research identified differences in the cyp transcriptome and cyp substrate depletion profile between the two species that suggests the need for speciesspecific. Comparisons between human and rodentinfecting species revealed differences in thiamine vitamin b1, choline, and pantothenate vitamin b5 metabolism. Species and strain differences in drug metabolism in liver. Tertiary oxidation of deoxycholate is conserved in preclinical animals article pdf available in drug metabolism and disposition 486. Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentrationtime relationships in the embryo. In rats, cytochrome p450 p450 iiia enzymes are an important determinant of digitoxin toxicity.
Git anatomy and physiology and drug oral bioavailability. Species differences between mouse, rat, dog, monkey and. However, developments in the last few years in the understanding of the genetic diversity of species, including man, in terms of biotransformation and the nature and substrate preferences of the various multiple forms of the drugmetabolizing enzymes now give a better insight into the nature of species differences of metabolism. In this paper, species differences in drug metabolizing enzymes and a method to predict human pharmacokinetics are explained. Abstract the prediction of human pharmacokinetics, efficacy, and toxicity from preclinical data remains an important goal in the drug discovery. Pharmaceutics free fulltext species differences in. Even within the same species, different strains of animals may show significant differences in drug metabolism. The contribution of rcyp2b11 in canine drug metabolism altered the rcyp metabolism pattern for 822 substrates compared to the cyp metabolism pattern reported for humans. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The complete breakdown of metabolites to carbon dioxide and water liberates. Pdf species differences in bloodbrain barrier transport of.
Pdf species differences in bloodbrain barrier transport. Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. In addition, the effect of cryopreservation was tested in perspective to the formation of a liver slice bank from rat, mouse, monkey, dog and human, allowing the easy comparison of qualitative differences in metabolic profiles both phase i and phase ii mediated metabolism of potential drug candidates among different species, including human. Drug metabolism monoxygenase enzymes p450 isozymes hydroxylation species differences da rat strain. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. The oral clearances cloral, doseaucoral in rats and dogs were, respectively, 300 and 18 times more than. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects cardiac failure causes decreased blood flow to the liver. In contrast, for drugs that are not or only partly. Comparative metabolism as a key driver of wildlife species. Species differences in the pharmacokinetic parameters of. Species differences in drug metabolism limit the value of preclinical in vivo studies.
Thus, differences in cyp isoforms between species are a major cause of species differences in drug metabolism. Species differences between mouse, rat, dog, monkey and human cypmediated drug metabolism, inhibition and induction 876 expert opin. The present study shows that the susceptibility of different mammalian species to digitoxin toxicity is inversely related to. This study was designed to compare brain uptake of three radiolabeled pglycoprotein pgp substrates across species using positron emission tomography. Indinavir exhibited marked species differences in elimination.
Species differences between mouse, rat, dog, monkey and human cypmediated drug metabolism, inhibition and induction martignoni et al. Species differences drug metabolism derick mussen healthcare. Chapter 8 covers essential information on drug metabolism for industrial scientists. Mar 12, 2020 sex differences in drug metabolism appear to be species dependent. When a nationalregional authority calls for a total residue and metabolism study for a minor.
Species differences in the toxicity and cytochrome p450 iiia. Imipramine and desmethylimipramine dmi in rats prevent and even reverse the sedative effects of reserpine and certain benzoquinolizines such as ro 41284. The firstpass effect after oral application is often more pronounced in animals than man. Such differences can be either of a quantitative same metabolic route although at different relative rates or qualitative different metabolic routes, different metabolites formed nature. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects. The possible range of p450 isozymes in significant variations in toxicity exhibited by experimental rodent species may have a relevance to chemical risk assessment, especially as human.
Substrates for n glucuronidation can be classified according to the chemical structures of the resulting glucuronides into two groups. Functional interrogation of plasmodium genus metabolism. Factors involved in species differences in drug metabolism and biochemical mechanisms of druginduced lesions, respectively obach, personal communication. Species difference an overview sciencedirect topics. The plasma concentrations of hsg4112s and hsg4112r were quantitated in plasma from rats and beagle dogs after iv andor oral administration of racemic hsg4112. One of the most complex challenges to the toxicologist represents extrapolation from laboratory animals to humans. Species and strain differences in drug metabolism in liver and intestine.
Species differences in the pharmacokinetics and metabolism. The antisedative effects of these compounds, however, are not as apparent in rabbit or mouse. Hsg4112, a racemic drug, is a new antiobesity agent. University of groningen species and strain differences in. Cyp isoforms between species are a major cause of species differences in drug metabolism. Korfmacheradvances in the integration of drug metabolism into the lead.
Disposition of the compound absorption of the compound through skin shows considerable species variation oral absorption depends upon ph of digestive tract herbivores vs. In this study, we demonstrated that there are large species differences in the. Pharmacokinetics, interactions with macromolecules and. Drug metabolism and pharmacokinetics in drug discovery. Apr 17, 2020 during its evolution, every animal species was under an individual selection pressure with regard to drug metabolism, in major part dictated by its preferred diet. Pdf species differences in pharmacokinetics and drug. The metabolism of drugs and foreign compounds is often different in different species. Experimental animals, such as mice, rats, dogs, monkeys, and.
Species differences in the pharmacokinetics of recainam, a. In vitro and in vivo small intestinal metabolism of cyp3a and. The 1971 gordon conference on drug metabolism opened with plenary lectures from two of the fields founders, r. Induction of these liver microsomal enzymes decreases the toxicity of digitoxin by increasing its oxidative cleavage to digitoxigenin bis and monodigitoxoside dt2 and dt1. Pdf species differences in the distribution of drug. Drugsguidancecomplianceregulatoryinformationguidancesucm079266. We encourage the identification of any differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible during the drug development process. Rabbits and mice, for example, do not show a significant sex difference in drug metabolism.
Although a relatively understudied area of research, over the last 20 years there has been considerable progress in understanding the molecular and genetic basis for differences in drug metabolism and disposition in cats compared with other species. Recent studies indicated that the individual, strain, sex and species differences in the rate of drug metabolism appear to be factors responsible for the individual, strain, sex and species differences in the effect and toxicity of a variety of drugs 2, 3, 6, 7. Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. Although it is generally believed that data from animal studies can be reasonably extrapolated to humans with the application of appropriate pharmacokinetic principles, there are certainly some limitations. Reproducing human and crossspecies drug toxicities using. Xenobiotic metabolism, which includes drug metabolism, has become. However, even small changes in amino acid sequences can give rise to marked differences in substrate specificity and catalytic activity. A range of factors may influence adme absorption, distribution, metabolism and excretion and other aspects of susceptibility to hazards. Cytochromes p450 and species differences in xenobiotic. Indinavir, a potent and specific inhibitor of human immunodeficiency virus protease, is undergoing clinical investigation for the treatment of acquired immunodeficiency syndrome. Significant species differences can exist in the enzyme induction response to a given chemical and also in the toxicological consequences of induction. Metabolic detoxification determines species differences in. Thus, species differences in cyp isoforms are a major cause of the differences reported in drug metabolism.
The reactions during this stage are responsible for converting more than 90 percent of the available food energy to a form that our bodies can use. Species similarities and differences in pharmacokinetics. Occurs in the cytosolic fraction of the liver cells 4, 6. Canine and feline differences in the cytochrome p450. Differences between species concerning the metabolism of the drugs may contribute to different pharmacokinetic properties in vivo after oral administration or injection graham and lake, 2008. O factors affecting drug metabolism pharmaceutical chemistry. In the process of drug development, animal experiments are inevitable but may not reflect accurately the human conditions due to species difference in drug disposition, especially metabolism. Early knowledge of the human metabolism of a new drug is desirable for two main reasons.
Species differences in plasma protein binding might also explain observed differences in pharmacokinetics especially for drugs that are highly bound. In this paper, species differences in drug metabolizing enzymes and a. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. Jan 27, 2012 animal models are commonly used in the preclinical development of new drugs.
Species differences between mouse, rat, dog, monkey. Species differences in the distribution of drugmetabolizing enzymes in the pancreas article pdf available in toxicologic pathology 302. Glucuronidation of amines has been shown to exhibit species differences in vitro and in vivo. Species and strain differences species differences in toxicity of a compound are related to differences in metabolism and disposition of the compound. Evidence presented in this paper indicates that differences in the metabolism of imipramine and dmi may partially explain the species variations. Therefore, this introduction is focused on a description of the main cyp. Factors affecting drug metabolism flashcards quizlet. Pdf species differences of bile acid redox metabolism. Influence of intra and interspecies differences in drug metabolism. Species differences in the induction of drug metabolism by.