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European Journal of Drug Metabolism and... Apr 2016Amino-noscapine is a promising noscapine derivative undergoing R&D as an efficient anti-tumor drug. In vitro phase I metabolism incubation system was employed. In vitro...
Amino-noscapine is a promising noscapine derivative undergoing R&D as an efficient anti-tumor drug. In vitro phase I metabolism incubation system was employed. In vitro samples were analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. In vitro recombinant CYP isoforms screening was used to identify the drug-metabolizing enzymes involved in the metabolism of amino-noscapine. Multiple metabolics were formed, including the formation of metabolite undergoing cleavage of methylenedioxy group, hydroxylated metabolites, demethylated metabolites, and metabolites undergoing C-C cleavage. Nearly, all the CYP isoforms were involved in the metabolism of metabolites II, III, VII, IX, and X. CYP1A1 was demonstrated to be the major CYP isoform for the formation of metabolites IV and V. CYP1A1 and CYP3A4 mainly catalyzed the formation of metabolite VI. The metabolic formation of VIII was mainly catalyzed by CYP2C19 and CYP3A4. CYP3A4 was the main enzyme for the formation of XI. CYP2C9 mainly catalyzed the generation of metabolite XII. In conclusion, the metabolic pathway of amino-noscapine was elucidated in the present study using in vitro phase I incubation experiment, including the structural elucidation of metabolites and involved phase I drug-metabolizing enzymes. This information was helpful for the R&D of amino-noscapine.
Topics: Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Humans; Metabolic Detoxication, Phase I; Microsomes, Liver; Noscapine; Spectrometry, Mass, Electrospray Ionization
PubMed: 25527252
DOI: 10.1007/s13318-014-0241-6 -
European Journal of Clinical... Dec 2008The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by... (Review)
Review
The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.
Topics: Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Humans; Inactivation, Metabolic; Liver; Liver Diseases; Metabolic Clearance Rate; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 18762933
DOI: 10.1007/s00228-008-0553-z -
Journal of Clinical Pharmacology Jan 1997The pharmacokinetics of many drugs often vary considerably among individuals, largely because of variations in the expression of different cytochrome P-450 (CYP) enzymes... (Review)
Review
The pharmacokinetics of many drugs often vary considerably among individuals, largely because of variations in the expression of different cytochrome P-450 (CYP) enzymes in the liver and other tissues. Relatively selective substrate probes in vivo have been discovered for several major CYP isoforms involved in oxidative drug metabolism. Regarding isoforms that show genetic polymorphism (CYP2C19 and CYP2D6), genotyping as well as phenotyping with appropriate probe drugs can be used to distinguish between "poor" and "extensive" metabolizers. Measurement of CYP2D6 activity, which is being performed increasingly by means of genotyping, has an established role in the individualization of the dosage of selected CYP2D6 substrates. However, the therapeutic implications of extremely high CYP2D6 activity in some patients (ultrarapid metabolizers) need more attention. The therapeutic consequences of CYP2C19 polymorphism are not as well characterized as those of CYP2D6 polymorphism, but are likely to be of little significance with most CYP2C19 substrates. Probe-based assays are also available for measurement of in vivo activity of CYP1A2, CYP2E1 and CYP3A4; those will be discussed in detail in this review. These tests can be used, for example, to compare the activity of a specific isoform among patients and to characterize effects of such environmental factors as drugs and compounds in the diet on enzyme activity. However, it should be recognized that attempts to develop valid probe-based assays of in vivo activity of specific, nonpolymorphic CYP isoforms have proved relatively difficult; for example, none of the several putative probes of CYP3A4, the most important drug-metabolizing CYP isoform, is completely satisfactory. It is now clear that many diverse factors must be considered in the validation of these tests.
Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Isoenzymes; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology, Clinical
PubMed: 9048284
DOI: 10.1177/009127009703700121 -
Biomedical Papers of the Medical... Jun 2010Phase II biotransformation reactions (also 'conjugation reactions') generally serve as a detoxifying step in drug metabolism. Phase II drug metabolising enzymes are... (Review)
Review
BACKGROUND
Phase II biotransformation reactions (also 'conjugation reactions') generally serve as a detoxifying step in drug metabolism. Phase II drug metabolising enzymes are mainly transferases. This review covers the major phase II enzymes: UDP-glucuronosyltransferases, sulfotransferases, N-acetyltransferases, glutathione S-transferases and methyltransferases (mainly thiopurine S-methyl transferase and catechol O-methyl transferase). The focus is on the presence of various forms, on tissue and cellular distribution, on the respective substrates, on genetic polymorphism and finally on the interspecies differences in these enzymes.
METHODS AND RESULTS
A literature search using the following databases PubMed, Science Direct and EBSCO for the years, 1969-2010.
CONCLUSIONS
Phase II drug metabolizing enzymes play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologically active compounds. Reduced metabolising capacity of Phase II enzymes can lead to toxic effects of clinically used drugs. Gene polymorphism/ lack of these enzymes may often play a role in several forms of cancer.
Topics: Animals; Biotransformation; Humans; Metabolic Detoxication, Phase II; Polymorphism, Genetic; Transferases; Xenobiotics
PubMed: 20668491
DOI: 10.5507/bp.2010.017 -
Drug Metabolism Reviews May 2019Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide.... (Review)
Review
Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem.
Topics: Animals; Drug Resistance; Enzymes; Humans; Inactivation, Metabolic; Pharmaceutical Preparations; Pharmacology
PubMed: 31203662
DOI: 10.1080/03602532.2019.1632886 -
Journal of Chronic Diseases 1983The kinetics of drugs are known to change in the elderly. The most unequivocal example is the decrease in renal drug clearance. Yet, few studies have been published on...
The kinetics of drugs are known to change in the elderly. The most unequivocal example is the decrease in renal drug clearance. Yet, few studies have been published on the renal clinically important impairment of drug metabolism occurs in the elderly, and the effect of age per se cannot easily be discerned because a number of other factors that affect drug metabolism change with age (dietary and smoking habits, disease, drug interactions, ect.). In each age group there is a marked interindividual variation in the metabolic clearance of drugs leading to pronounced differences in steady-state plasma concentrations at fixed dosage-schedules. For drugs with a narrow therapeutic range it is important to avoid standard doses in slow metabolizers. This phenotype is at risk to develop adverse drug reactions unless the dose is reduced. It may be particularly important to recognize the slow metabolizer phenotype among the elderly, who may have exaggerated drug response due to physiological and pharmacodynamic reasons.
Topics: Aged; Aging; Enzymes; Humans; Kidney; Kinetics; Metabolic Clearance Rate; Models, Genetic; Pharmaceutical Preparations; Phenotype
PubMed: 6848546
DOI: 10.1016/0021-9681(83)90040-1 -
Drug Metabolism and Disposition: the... Jun 2019Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs)...
Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human induced pluripotent stem cells (human iPS cells) and our highly efficient genome-editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research. The gene expression levels of hepatocyte markers were similar between wild-type iPS cell-derived hepatocyte-like cells (WT HLCs) and CYP2C19-KO HLCs, suggesting that CYP2C19 deficiency did not affect the hepatic differentiation potency. We also examined CYP2C19 metabolic activity by measuring -mephenytoin metabolites using ultra-performance liquid chromatography-tandem mass spectrometry. The CYP2C19 metabolic activity was almost eliminated by CYP2C19 knockout. Additionally, we evaluated whether clopidogrel (CYP2C19 substrate)-induced liver toxicity could be predicted using our model. Unexpectedly, there was no significant difference in cell viability between clopidogrel-treated WT HLCs and CYP2C19-KO HLCs. However, the cell viability in clopidogrel- and ketoconazole (CYP3A4 inhibitor)-treated CYP2C19-KO HLCs was significantly enhanced as compared with that in clopidogrel- and DMSO-treated CYP2C19-KO HLCs. This result suggests that CYP2C19-KO HLCs can predict clopidogrel-induced liver toxicity. We succeeded in generating CYP2C19 PM model cells using human iPS cells and genome-editing technologies for pharmaceutical research. SIGNIFICANCE STATEMENT: Although unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 poor metabolizers, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 poor metabolizers because there is currently no model for this phenotype. Using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells as a novel CYP2C19 poor metabolizer model for drug development and research.
Topics: Cell Differentiation; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Clopidogrel; Cytochrome P-450 CYP2C19; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Ketoconazole; Liver; Metabolic Clearance Rate
PubMed: 30962288
DOI: 10.1124/dmd.119.086322 -
Drug Metabolism Reviews 2007The mammalian skin has long been considered to be poor in drug metabolism. However, many reports clearly show that most drug metabolizing enzymes also occur in the... (Review)
Review
The mammalian skin has long been considered to be poor in drug metabolism. However, many reports clearly show that most drug metabolizing enzymes also occur in the mammalian skin albeit at relatively low specific activities. This review summarizes the current state of knowledge on drug metabolizing enzymes in the skin of human, rat, and pig, the latter, because it is often taken as a model for human skin on grounds of anatomical similarities. However only little is known about drug metabolizing enzymes in pig skin. Interestingly, some cytochromes P450 (CYP) have been observed in the rat skin which are not expressed in the rat liver, such as CYP 2B12 and CYP2D4. As far as investigated most drug metabolizing enzymes occur in the suprabasal (i.e. differentiating) layers of the epidermis, but the rat CYP1A1 rather in the basal layer and human UDP-glucuronosyltransferase rather in the stratum corneum. The pattern of drug metabolizing enzymes and their localization will impact not only the beneficial as well as detrimental properties of drugs for the skin but also dictate whether a drug reaches the blood flow unchanged or as activated or inactivated metabolite(s).
Topics: Animals; Cells, Cultured; Cytochrome P-450 Enzyme System; Enzymes; Humans; Isoenzymes; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Organ Culture Techniques; Pharmaceutical Preparations; Rats; Skin; Species Specificity; Swine
PubMed: 18058329
DOI: 10.1080/03602530701690366 -
Yakugaku Zasshi : Journal of the... 2019Human hepatocytes possess a wider range of phase I and II drug-metabolizing enzyme activities than other liver tissue-derived products, such as human liver microsomes.... (Review)
Review
Human hepatocytes possess a wider range of phase I and II drug-metabolizing enzyme activities than other liver tissue-derived products, such as human liver microsomes. Thus, hepatocytes may be useful for predicting the in vivo metabolic fate of new drugs of abuse in humans. Recently, new types of human hepatocytes have been made commercially available for use in drug metabolism studies, such as a liver tumor-derived cell line (HepaRG), and a human induced pluripotent stem cell-derived hepatocyte (h-iPS-HEP). In our laboratory, HepaRG has been used to elucidate the metabolic pathways of XLR-11, a synthetic cannabinoid, and its thermal degradant. In addition, the potential of h-iPS-HEP to metabolize drugs was assessed using fentanyl as a model drug, and indeed, h-iPS-HEP exhibited a pattern for fentanyl metabolite formation similar to that observed in vivo. In addition, the phase I and II drug-metabolizing enzyme activities of HepaRG, h-iPS-HEP, liver-humanized mouse-derived hepatocytes (PXB-cellsTM), and human primary hepatocytes were evaluated and compared. HepaRG showed high phase I and II drug metabolism activities; however, the CYP2D6 activity in these cells was quite low, and therefore h-iPS-HEP lacked O-methylation and conjugation activities. PXB-cells provided optimal results, i.e., these cells are extremely easy to use, and they possess higher phase I and II drug-metabolizing enzyme activities than the other cells tested. Although PXB-cells are contaminated with mouse-derived cells up to a concentration of several percent, this cell system appears to be promising for the prediction of in vivo human metabolism of new drugs of abuse.
Topics: Animals; Cannabinoids; Cell Line; Cytochrome P-450 CYP2D6; Fentanyl; Hepatocytes; Humans; Methylation; Mice; Substance-Related Disorders
PubMed: 31061338
DOI: 10.1248/yakushi.18-00166-3