Factors affecting metabolism physico chemical factors enzyme induction enzyme inhibition environmental chemicals biologic factors species differences strain differences age, sex diet altered physiological factors pregnancy hormonal imbalance disease state molecular size and shape pka acidity basicity lipophilicity stereo chemical nature of drug. Even within the same species, different strains of animals may show significant differences in drug metabolism. Our results indicate that variability in the formation of 5oxozal from zal in vivo in various strains of rats is primarily due to strain differences of hepatic aldehyde oxidase activity. 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. Integrated multilaboratory systems biology reveals differences in protein metabolism between two reference yeast strains. The inbred strains of rodents, however, remain a model for genetic differences in other species. Therefore, there is a need to understand similarities and differences in drug disposition of these mouse strains with respect to drug disposition. However, conclusively measuring target engagement te in situ is challenging. However, even small changes in the amino acid sequences can give rise to profound differences in substrate specificity and catalytic activity. Marked strain differences in the pharmacokinetics of an. Drug metabolism in the elderly more than 65 years old is of particular interest since this group is forming an increasingly larger part of the population. The basis for straindependent rat aldehyde dehydrogenase 1a7.
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. Provide information on mechanisms of action of a drug provides an early indication of the potential for some kinds of toxic effects, allowing a decision to terminate a development program before spending too much money. This finding has implications for the design and interpretation of pharmacological and toxicological studies on the effects and disposition of aldehydes. Factors that contribute to the differences include presence and amount of salivary amylase. While the major differences in hepatic metabolism were attributable to the strain of animal, sex effects were also observed. Gender differences in drug metabolism regulated by growth hormone gender differences in drug metabolism regulated by growth hormone shapiro, bernard h agrawal, arun k pampori, nisar a.
Lack of strainrelated differences in drug metabolism and efflux transporter characteristics between cd1 and athymic nude mice march 2005 cancer chemotherapy and pharmacology 552. Significance statement genetic variation in rat aldh1a7 promoter sequences underlie the large straindependent differences in expression and inducibility by phenobarbital of the aldehyde dehydrogenase activity. Hepatic phase i and phase ii metabolism of a set of well known substrates in microsomes andor liver slices demonstrated close similarity between the two strains. Both drug metabolism and drug transporters are important features that determine the disposition of drugs.
Cannabis strains are either pure or hybrid varieties of the plant genus cannabis, which encompasses the species c. The metabolism of drugs and foreign compounds is often different in different species. 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. Impact of species and strain selection on drug development programs differences in types and incidence of neoplasms in wistar han and spraguedawley rats klaus weber1 abstract a substantial quantity of data on spraguedawley sd and hannover wistar rats strains have been published concerning their. Among aldhs, the rat aldh1a7 gene displays a curious strain dependence in phenobarbital pbinduced hepatic expression. Cytochrome p450 cyp is one of the key enzymes in drug metabolism.
In silico and in vitro pharmacogenetic analysis in mice pnas. Mar 07, 2014 conclusion the therapeutic efficacy, toxicity and biological halflife of a drug greatly depends on the metabolism of the drug and a number of factors affect the metabolism of the drug. Influence of strain differences in mice on the metabolism and toxicity of. Several reports concerning differences in xenobiotic metabolism and toxicity among inbred strains of mice prompted us to study benzene metabolism and toxicity in c57bl 6 and dba 2 mice. The current research draws on classical and general strain theories to explain drug and alcohol use in canada, using a general population sample. This complicates preclinical development and is considered a key factor in the high rate of attrition. Numerous studies conducted in 1970s and 1980s highlighted the influence of intestinal microbiota on drug metabolism rowland, 1986. Strain and sex differences in drug hydrolase activities in. Strain differences differences observed in the metabolism of a drug among different races are called as ethnic variations.
Therefore, the important question is raised which factors determine the role of intestinal metabolism in the firstpass effect. Thus differences in cyp isoforms between species are a major cause of species differences in drug metabolism. Mitchell b a school of biosciences, university of birmingham, birmingham, uk b computational and systems medicine, imperial college london, london, uk highlights drug metabolism in healthy old age is similar to that found in young adults. To gain an insight into possible strainrelated differences in drug metabolism and drug transporters between cd1 and athymic nude mice, we. Lack of strain related differences in drug metabolism and efflux transporter characteristics between cd1 and athymic nude mice march 2005 cancer chemotherapy and pharmacology 552.
The efficacy of ldopa treatment for parkinsons disease is hugely variable between individuals, depending on the composition of their microbiota. The crossover point between drug discovery and drug development. Aug, 2017 the marked strain differences in the mouse have also been extended to include differences in the induction of drug metabolism. Therefore, differences in expression between species of the most important family of drug metabolizing enzymes, the cytochrome p450s cyps are a major cause. These inbred strains act as models for other genetic variations in drug metabolism. Hepatic and extrahepatic metabolism of deprenyl, a. Toxicology and applied pharmacology 60, 398409 1981 influence of strain differences in mice on the metabolism and toxicity of benzene. However, the molecular basis for these differences has not been clearly understood. Gender differences in drug metabolism regulated by growth.
Unexpectedly, the presence of this enzyme in gut bacterial genomes did not correlate with dopamine metabolism. Influence of strain differences in mice on the metabolism and toxicity. The levels of 5oxozal in blood were closely correlated with the strain differences of cytosolic zal hydroxylase activity and benzaldehyde oxidase activity. The microbiota represent a significant route for metabolism of drugs and other xenobiotics and can significantly increase the halflife of xenobiotics in the body by hydrolysis and consequent reabsorption. Knowledge of strain differences in drug metabolism is important for the selection of animals for pharmacokinetic, pharmacodynamic, and toxicological studies. Transcriptomics linked this activity to a molybdenum cofactordependent dopamine dehydroxylase dadh enzyme. The marked strain differences in the mouse have also been extended to include differences in the induction of drug metabolism.
Clinical frontiers drug metabolism 2062 am j healthsyst pharmvol 59 nov 1, 2002 tional individualized therapeutics and patient care. Variation in gut microbiota strongly influences individual. Conclusion the therapeutic efficacy, toxicity and biological halflife of a drug greatly depends on the metabolism of the drug and a number of factors affect the metabolism of the drug. Differences among patients in drug metabolism in the intestine and liver are common, are often marked. There are strain and sex differences in the metabolic potencies of compounds among rodents, as has been reported for various drugmetabolizing enzymes, including cytochrome p450 cyp.
Species and strain differences in drug metabolism in liver and intestine. Aldehyde hydrogenases aldhs belong to a large gene family involved in oxidation of both endogenous and exogenous compounds in mammalian tissues. The classical example of strain differences in drug metabolism is that of. Drug metabolism in animals may be drastically different from that in humans hence the need for clinical trials ii. The animals used in this study were 8 to 12weekold male rats from the ss, bn, bn. In this investigation, we have found that sensitivity to chcl3 correlates with the capacity of the kidney to metabolize chcl3 to the toxic metabolite. Hemodynamic depression is a side effect of general anesthetics that has been managed by anesthesiologists for decades, but clinicians also recognize significant variations in cardiovascular sensitivity to these agents. For this, in vitro model systems, combined with sensitive analytical techniques and with analysis of gene expression were. Pharmacogenomic strain differences in cardiovascular. Strain differences in the liver microsomal metabolism of. A drug must engage its intended target to achieve its therapeutic effect. Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation, reduction, hydrolysis, hydration, conjugation, and migration. Kocsis, and robert snyder department of pharmacology, thomas jefferson university. Therefore, information on possible strain differences between cd1 and athymic nude mice which may affect the drug disposition of new chemical entities would be extremely useful.
Strain differences in drug metabolism exist, particularly in inbred mice and rabbits. Modulation of drug metabolism, but also of drug transporters may increase the risk of toxicity and other adverse drug reactions. Sep 22, 2004 cd1 mice are commonly used in oncology metabolism and toxicity to support drug discovery and development and to examine drug metabolism and toxicity properties of new chemical entities. Variety names are typically chosen by their growers, and often. For example, diazepam is mainly metabolized to p hydroxydiazepam by cyp2d1 in spraguedawley sd rats, whereas it is metabolized to 3hydroxydiazepam by cyp3a2 in dark agouti rats saito et al. Jan 22, 2016 cytochrome p450 cyp is one of the key enzymes in drug metabolism. While the relationship between strain and drug use has been explored, few studies have examined how it may be related to alcohol use and most have analyzed school aged and university samples.
Pdf lack of strainrelated differences in drug metabolism and. Ethylene glycol toxicity production of oxalic acid is in order. Although the laboratory rat rattus norvegicus has been widely used in the many science fields, including pharmacology and toxicology, it is well known that there are inter strain differences in cyp in terms of their nucleotide sequence, mrna and protein expression, as well as their enzymatic activity. A further aim of this thesis was to evaluate possible differences between strains of mice, commonly used in pharmacological studies, which may affect the drug disposition of new chemical entities.
Chronic benzene exposure results in a progressive depression of bone marrow function and is thought to be caused by a metabolite of benzene snyder and kocsis, 1975. These differences apparently are caused by genetic variations in the amount of metabolizing enzyme present among the different strains. Strain differences in the liver microsomal metabolism of the. Hepatic microsomes from spraguedawley sd and brown norway bn rats had 300fold higher diazepam p hydroxylation activity than dark agouti da and wistar w rats at a low diazepam concentration 3. Hepatic and extrahepatic metabolism of deprenyl, a selective. Cd1 mice are commonly used in oncology metabolism and toxicity to support drug discovery and development and to examine drug metabolism and toxicity properties of new chemical entities. The amount of warfarin and 9 identified metabolites in plasma was quantitated after dosing inbred mouse strains. Implications of these findings to drug action and to the development of new drugs are discussed.
The expression of cyp genes is regulated by physiological, genetic, and environmental factors. Imamichi strain and the lowest activity in the slc. Species and strain differences in drug metabolism in liver. Remarkably large strain differences were observed with approximately a 230 variation between the highest activity in the wistar. It is well known that various animal species react differently to.
Strainspecific differences in drug metabolism through generation of 7hydroxywarfarin metabolites were computationally correlated with genetic variation within a chromosomal region encoding cytochrome p450 2c enzymes. Influence of strain differences in mice on the metabolism and. In the first chapter, the principles underlying drug absorption, distribution, metabolism and elimination are described, with drug metabolism highlighted within the context of these fundamental processes. For this reason the toxicologist may have to consider both species and strain differences in metabolism when attempting to extrapolate findings to man in the safety evaluation process. Although the laboratory rat rattus norvegicus has been widely used in the many science fields, including pharmacology and toxicology, it is well known that there are interstrain differences in cyp in terms of their nucleotide sequence, mrna and protein expression, as well as their enzymatic activity. The experimental anticancer drug 5,6dimethylxanthenone4acetic acid dmxaa is mainly metabolised by acyl glucuronidation and to a lesser degree by 6methyl hydroxylation. Strain specific differences in drug metabolism through generation of 7hydroxywarfarin metabolites were computationally correlated with genetic variation within a chromosomal region encoding cytochrome p450 2c enzymes. Sd strain rats were considerably low, and that of the f344ducrj strain was very low. Study 20 terms factors affecting drug metabolism flashcards.
Dec 21, 2010 integrated multilaboratory systems biology reveals differences in protein metabolism between two reference yeast strains. However, significant differences in susceptibility to the same. Toxicologic pathology differences in types and incidence the. University of groningen species and strain differences in drug. On the other hand, athymic nude mice are the preferred animals to investigate tumor growth inhibition. Pdf lack of strainrelated differences in drug metabolism. Profound species differences exist in the gi tract, and all facets of the gi tract are important in drug absorption and metabolism. The contribution of the small intestine to overall drug metabolism is difficult to evaluate. The pharmacogenetic differences in a number of phasei enzymes, such as cytochrome p450 cyp isoenzymes, dehydrogenases, and esterases, and phaseii conjugating enzymes have been extensively studied. People are living longer thanks to modern drug discoveries and to polypharmacy where individuals have multiple. Using general strain theory to understand drug and alcohol. Using two strains of mouse it was shown that one strain c57 responds to treatment with 3methylcholanthrene 3mc, a polycyclic hydrocarbon inducer of aryl hydrocarbon hydroxylase whilst the other strain dba does not.
Sep 01, 2005 numerous studies conducted in 1970s and 1980s highlighted the influence of intestinal microbiota on drug metabolism rowland, 1986. Therefore, differences in expression between species of the most important family of drug metabolizing enzymes, the cytochrome p450s cyps are a major cause of species differences in drug metabolism. Strain differences in the maximum tolerated dose mtd of dmxaa in mice have been observed. For the past twenty years, work on species differences in metabolism has been largely of a descriptive nature and the cataloguing of differences. These results suggest that differences in compartmental phosphorylation states may be indicative of a greater lipogenic capacity of these rats compared to. Discoveryand inhibition of an interspecies gut bacterial.
These results suggest that differences in compartmental phosphorylation states may be indicative of a greater lipogenic capacity of these rats compared to normal rats. Toxicologic pathology differences in types and incidence. Basic overview of preclinical toxicology animal models. Strain differences in cytochrome p450 mrna and protein.
Cytochrome p450 enzymes cyp play a critical role in the oxidative metabolism of a variety of endogenous and exogenous compounds, including most drugs. Jun 17, 2019 figure 1 studying drug metabolism by gut bacteria. The research described in this thesis was aimed to investigate interspecies differences in drug metabolism. Integrated multilaboratory systems biology reveals. Such strain differences are referred to as genetic polymorphism. Drug metabolism in the elderly university of birmingham. The liver is the primary site for drug metabolism and contains the necessary enzymes for metabolism of drugs and other xenobiotics. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. University of groningen species and strain differences in. Sex differences in the hepatic metabolism of deprenyl to amphetamines were seen in all three strains of rats, spraguedawley, wistar and donryu. The basis for straindependent rat aldehyde dehydrogenase.
Microbes make metabolic mischief by targeting drugs. Influence of strain differences in mice on the metabolism. Strain differences were also seen in the metabolism of deprenyl, depending on the tissues and metabolites examined. It has been known for many years that there are species, strain, and sex differences in the incidence and severity of the nephrotoxicity caused by chloroform. Lack of strainrelated differences in drug metabolism and efflux transporter. Chapters 2 and 3 deal with the chemistry of drug biotransformation. Lack of strainrelated differences in drug metabolism and. Department of drug metabolism and pharmacokinetics, astrazeneca, mereside, alderley park, macclesfield sk10 4tg, uk. To address this issue, we characterized drug metabolism and efflux transporter properties in both strains and in different organs. Jun 14, 2019 the efficacy of ldopa treatment for parkinsons disease is hugely variable between individuals, depending on the composition of their microbiota. Hence various factors affecting drug metabolism must be considered during administration and also in proper dosing of any drug to the patients. Drug interactions resulting in either inhibition or induction of the involved enzymes, especially those in the intestinal epithelium, can markedly alter oral bioavailability fig.
Effect of sex on the strain differences in hepatic. 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. Effect of sex on the strain differences in hepatic metabolism. However, no sex differences observed in the extrahepatic metabolism of deprenyl.
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