Differences among species in rates of aging are believed to be attributable to differences in metabolic rates and associated cumulative oxidative injury. Pdf animal models are commonly used in the preclinical development of new drugs to predict the. Drugs guidancecomplianceregulatoryinformationguidancesucm079266. Species differences drug metabolism derick mussen healthcare. Species differences in the distribution of drugmetabolizing enzymes in the pancreas article pdf available in toxicologic pathology 302.
Functional interrogation of plasmodium genus metabolism identifies species and stagespecific differences in nutrient essentiality and drug targeting alyaa m. Jan 27, 2012 animal models are commonly used in the preclinical development of new drugs. 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. Species and strain differences in drug metabolism in liver. In rats, cytochrome p450 p450 iiia enzymes are an important determinant of digitoxin toxicity. Species differences between mouse, rat, dog, monkey.
Hsg4112, a racemic drug, is a new antiobesity agent. The present study shows that the susceptibility of different mammalian species to digitoxin toxicity is inversely related to. Species differences in coumarininduced hepatotoxicity were first described more than 40 years ago hazleton et al. Abstract the prediction of human pharmacokinetics, efficacy, and toxicity from preclinical data remains an important goal in the drug discovery. The 1971 gordon conference on drug metabolism opened with plenary lectures from two of the fields founders, r. Interspecies difference in drug metabolism is a major factor accounting for species differences in pk and also in pd production or not of active metabolites. 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. Species and strain differences in drug metabolism in liver and intestine. Strategies for in vitro metabolic stability testing christopher patten, phd bd biosciences december 2, 2009. Patient variability largely due to differences in drug metabolism capacity.
Absorption, distribution, metabolism, and elimination. Rabbits and mice, for example, do not show a significant sex difference in drug metabolism. The antisedative effects of these compounds, however, are not as apparent in rabbit or mouse. Pdf species differences between mouse, rat, dog, monkey and. 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. 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 bioavailability after oral administration of s2,8dimethyl3methylene1oxa8azaspiro 4,5 decaneltartarate monohydrate ym796, which is being developed as an antidementia drug, at a dose of 1 mgkg was very low 3. Comparisons between human and rodentinfecting species revealed differences in thiamine vitamin b1, choline, and pantothenate vitamin b5 metabolism. Safety testing of drug metabolites guidance for industry.
Unlimited viewing of the articlechapter pdf and any associated supplements and figures. Abstract nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. A range of factors may influence adme absorption, distribution, metabolism and excretion and other aspects of susceptibility to hazards. In vitro and in vivo small intestinal metabolism of cyp3a and ugt substrates in preclinical animals species and humans. Functional interrogation of plasmodium genus metabolism. Species differences in metabolism and pharmacokinetics. In contrast, for drugs that are not or only partly metabolized, species differences seem smaller and cross species pharmacokinetics can be predicted very well by allometric scaling. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Molecular mechanisms for species differences in organic.
Species differences in the pharmacokinetics of recainam, a new anti. 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. Species differences in the induction of drug metabolism by rifampicin.
Canine and feline differences in the cytochrome p450. In this paper, species differences in drug metabolizing enzymes and a. The plasma concentrations of hsg4112s and hsg4112r were quantitated in plasma from rats and beagle dogs after iv andor oral administration of racemic hsg4112. These are due largely to alterations in isoform composition, regulation, expression, and catalytic activities of drug. The metabolism and disposition characteristics of na were linear in male and female mice over a dose range of 20 to 500 mgkg. The oral clearances cloral, doseaucoral in rats and dogs were, respectively, 300 and 18 times more than. Pharmacokinetics, interactions with macromolecules and. Species differences in drug metabolism species differences in drug metabolism hucker, h b 19700401 00. Korfmacheradvances in the integration of drug metabolism into the lead. The importance of cytochrome p450 isoforms to species differences in the metabolism of foreign compounds and activation of procarcinogens has been identified. Species differences in drug metabolism n nn h 2n nh 2 n ho n n h 2n nh 2 ho h n nn o h 2n nh 2 oh oh n nh 2 h 2n nh 2 nh 2h hn nh 2 oh oh oh ch 3 o 50% human 6% rat 5% guinea pig 2% mouse 10% human 12% rat 2% guinea pig 6% human 3% rat 7% guinea pig 1% mouse trace amounts in all animals phenazopyridine pap 5oh pap 5, 4 diohpap 4 ohpap. Cyp isoforms between species are a major cause of species differences in drug metabolism.
For compounds of the former classsuch as sulfonamides. Thus, some major species differences in drug metabolism68,69 may tentatively be rationalized by speciesspecific requirements. Species differences in the toxicity and cytochrome p450 iiia. Small amounts of unchanged pm hence the need for clinical trials ii. Cytochromes p450 and species differences in xenobiotic. 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. O factors affecting drug metabolism pharmaceutical chemistry. Drug metabolism monoxygenase enzymes p450 isozymes hydroxylation species differences da rat strain. Species differences in nglucuronidation drug metabolism. Factors involved in species differences in drug metabolism and biochemical mechanisms of druginduced lesions, respectively obach, personal communication. The study demonstrated that obesity can alter enzyme activity in a species and model dependent manner. Thus, species differences in cyp isoforms are a major cause of the differences reported in drug metabolism. Phenylalanine methyl ester pm is a decomposition product of the sweetening agent aspartame.
Thus, some major species differences in drug metabolism68,69 may tentatively be rationalized by species specific requirements. Excretion rate of urine excretion varies considerably between species in rat 10 times higher than that of humans. Small animal clinical pharmacology and therapeutics. Imipramine and desmethylimipramine dmi in rats prevent and even reverse the sedative effects of reserpine and certain benzoquinolizines such as ro 41284. Pdf species differences in the distribution of drug. Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. Species differences in drug metabolism dr ted williams. Animal models are commonly used in the preclinical development of new drugs. 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. 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. Species differences between mouse, rat, dog, monkey and human.
Species and strain differences disposition of the compound distribution the plasma protein concentration is a species dependent variable, also types of proteins vary between species. Species differences variations in primary sequence of cyp between species can result in differences in substrate specificityactivity levels of cyp isoforms may differ between species interspecies differences in enzyme inhibition cannot make crossspecies predictions regarding metabolic stability. 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 drug metabolizing enzymes now give a better insight into the nature of species differences of metabolism. Subsequently, a large body of work describing the in vitro and in vivo metabolism of coumarin in many species has been developed. Drugsguidancecomplianceregulatoryinformationguidancesucm079266. The cyp families 1, 2 and 3 appear to be responsible for the metabolism of drugs and other xenobiotics, but they are also involved in metabolic conversion of a. Pdf species differences in bloodbrain barrier transport.
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. Substrates for n glucuronidation can be classified according to the chemical structures of the resulting glucuronides into two groups. Variations in primary sequence of cyp between species can result in differences in substrate specificityactivity. An other possibility is that, in some cases at least, urinary excretion patterns of metabolites in several species are not truly reflecting the metabolic differ ences at. Although this work has generated important information about coumarin metabolism across. Linspecies similarities and differences in pharmacokinetics. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. This study was designed to compare brain uptake of three radiolabeled pglycoprotein pgp substrates across species using positron emission tomography. Glucuronidation of amines has been shown to exhibit species differences in vitro and in vivo. In this study, we demonstrated that there are large species differences in the.
Results of this study suggest that the species and tissuedependent differences in carcinogenicity of na were associated with differences in metabolism and disposition between the two. Contains hepatic drugmetabolising enzymes cytochrome p450 referred to as cyp 1, 2. Species differences in the disposition and metabolism of. Influence of intra and interspecies differences in drug metabolism. Pdf prediction of species differences rats, dogs, humans. 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. Species differences in the pharmacokinetics of recainam, a. Species differences between mouse, rat, dog, monkey and human cypmediated drug metabolism, inhibition and induction 876 expert opin.
Reproducing human and crossspecies drug toxicities using. However, even small changes in amino acid sequences can give rise to marked differences in substrate specificity and catalytic activity. Pharmaceutics free fulltext species differences in. Species differences in the toxicity and cytochrome p450. West point, pennsylvania introducrion the importance of species differences in drug metabolism in understanda ing the mechanism of action of many drugs has become increasingly evia dent. Evidence presented in this paper indicates that differences in the metabolism of imipramine and dmi may partially explain the species variations. Significant species differences can exist in the enzyme induction response to a given chemical and also in the toxicological consequences of induction. Intestinal firstpass metabolism has a great impact on the bioavailability of cytochrome p450 3a4 cyp3a andor uridine 5. Occurs in the cytosolic fraction of the liver cells 4, 6. Brain concentrations and braintoplasma ratios were compared. 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. Hepatic cyp form induction in humans may lead to clinically important drugdrug interactions.
Induction of these liver microsomal enzymes decreases the toxicity of digitoxin by increasing its oxidative cleavage to digitoxigenin bis and monodigitoxoside dt2 and dt1. 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 between mouse, rat, dog, monkey and. In vitro and in vivo intestinal metabolism studies are essential for clarifying pharmacokinetics in animal species and for predicting the effects of human intestinal metabolism. Mar 12, 2020 sex differences in drug metabolism appear to be species dependent. 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. Results support using multispecies chips to identify speciesspecific differences in drug metabolism and toxicity. 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. Nalidixic acid na is an antimicrobial drug that has been used to treat urinary tract infections.
Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. 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. Abdelhaleem, roles data curation, formal analysis, investigation, methodology, visualization, writing original draft. Therefore, this introduction is focused on a description of the main cyp. Early knowledge of the human metabolism of a new drug is desirable for two main reasons. Pdf species differences in bloodbrain barrier transport of. Occurs in the smooth endoplasmic reticulum ser of the liver cells 2. In vitro and in vivo small intestinal metabolism of cyp3a. Species differences in drug metabolism hucker, h b 19700401 00. The potential for absorption of pm was examined following intragastric and intraduodenal administration of 20mg doses of 14 cpm to rhesus monkeys implanted with hepatic portal vein cannulae. The study indicated species dependent differences in clint of various drugs that were due to, either changes in expression of drug metabolizing enzymes or changes in enzyme substrate affinity.
In vitro and in vivo small intestinal metabolism of cyp3a and. University of groningen species and strain differences in. Metabolic detoxification determines species differences in. Strategies for in vitro metabolic stability testing. Sex differences in drug metabolism appear to be species dependent.
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