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Drug Metabolism Reviews Nov 2017Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural... (Review)
Review
Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.
Topics: Animals; Biological Products; Biopharmaceutics; Humans; Metabolic Networks and Pathways; Permeability
PubMed: 28911247
DOI: 10.1080/03602532.2017.1377222 -
Critical Reviews in Oncology/hematology Jun 2017Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this... (Review)
Review
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Energy Metabolism; Humans; Pancreatic Neoplasms
PubMed: 28477742
DOI: 10.1016/j.critrevonc.2017.03.026 -
Current Drug Metabolism 2021In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of... (Review)
Review
In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic, and the opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered as the center of biotransformation reactions because the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalyzed by mitochondria where it is both an initiator and target of toxicity.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Mitochondria; Pharmaceutical Preparations; Xenobiotics
PubMed: 34182906
DOI: 10.2174/1389200222666210628125020 -
Current Opinion in Gastroenterology May 2015It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests... (Review)
Review
PURPOSE OF REVIEW
It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high-affinity hepatic transporters exhibit high 'first-pass' hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways.
RECENT FINDINGS
We highlight one quantitative liver function test, the dual cholate test, and introduce the concept of a disease severity index linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting.
SUMMARY
It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy.
Topics: Cholates; Health Services Needs and Demand; Hepatocytes; Humans; Liver; Liver Diseases; Liver Function Tests; Metabolic Clearance Rate; Predictive Value of Tests; Severity of Illness Index
PubMed: 25714706
DOI: 10.1097/MOG.0000000000000167 -
Clinical & Translational Oncology :... Oct 2020Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach... (Review)
Review
Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach the fruitful results. There are many causes for this resistance that are being studied by the researchers across the world, but still, success is far because there are several factors that are going along unattended or have been studied less. Drug-metabolizing enzymes (DMEs) are one of these factors, on which less study has been conducted. DMEs include Phase I and Phase II enzymes. Cytochrome P450s (CYPs) are major Phase I enzymes while glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), dihydropyrimidine dehydrogenases are the major enzymes belonging to the Phase II enzymes. These enzymes play an important role in detoxification of the xenobiotics as well as the metabolism of drugs, depending upon the tissue in which they are expressed. When present in tumorous tissues, they cause resistance by metabolizing the drugs and rendering them inactive. In this review, the role of these various enzymes in anticancer drug metabolism and the possibilities for overcoming the resistance have been discussed.
Topics: Antineoplastic Agents; Catalysis; Cytochrome P-450 Enzyme System; Dihydrouracil Dehydrogenase (NADP); Drug Resistance, Neoplasm; Glucuronosyltransferase; Glutathione Transferase; Humans; Inactivation, Metabolic; Neoplasms
PubMed: 32170639
DOI: 10.1007/s12094-020-02325-7 -
Drug Metabolism Reviews Aug 2022Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are... (Review)
Review
Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are relatively well-characterized; however, their metabolizing enzymes have not been fully explored. UDP-glucuronosyltransferases, 3--acetyltransferase, and glutathione -transferase are involved in the formation of DON-glucuronides, 3-acetyl-DON, and DON-glutathione, respectively. There are interindividual differences in the metabolism of these toxins, including variation with respect to sex. Furthermore, interspecies differences in DON metabolism have been revealed, including differences in the major metabolites of DON, the role of de-acetylation, and the hydrolysis of DON-3G. In this review, we summarized the major enzymes involved in metabolizing DON to its modified forms, focusing on the differences in metabolism of DON and its modified forms between individuals and species. This work provides important insight into the toxicity of DON and its derivatives in humans and animals, and provides scientific basis for the development of safer and more efficient biological detoxification methods.
Topics: Animals; Glucuronides; Glucuronosyltransferase; Humans; Hydrolysis; Inactivation, Metabolic; Trichothecenes
PubMed: 35695207
DOI: 10.1080/03602532.2022.2088786 -
Current Neuropharmacology 2019Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a... (Review)
Review
BACKGROUND
Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways.
METHODS
CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions.
RESULTS
The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype.
CONCLUSION
Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy.
Topics: Adult; Age Factors; Anticonvulsants; Biosynthetic Pathways; Child; Cytochrome P-450 CYP2C9; Epilepsy; Genotype; Humans; Phenotype; Polymorphism, Genetic; Valproic Acid
PubMed: 29119932
DOI: 10.2174/1570159X15666171109143654 -
Drug Metabolism Reviews May 2015This article reviews in vitro metabolic activities [including Michaelis constants (Km), maximal velocities (Vmax) and Vmax/Km] and drug-steroid interactions [such as... (Review)
Review
This article reviews in vitro metabolic activities [including Michaelis constants (Km), maximal velocities (Vmax) and Vmax/Km] and drug-steroid interactions [such as induction and cooperativity (activation)] of cytochromes P450 (P450 or CYP) in human tissues, including liver and adrenal gland, for 14 kinds of endogenous steroid compounds, including allopregnanolone, cholesterol, cortisol, cortisone, dehydroepiandrosterone, estradiol, estrone, pregnenolone, progesterone, testosterone and bile acids (cholic acid). First, we considered the drug-metabolizing P450s. 6β-Hydroxylation of many steroids, including cortisol, cortisone, progesterone and testosterone, was catalyzed primarily by CYP3A4. CYP1A2 and CYP3A4, respectively, are likely the major hepatic enzymes responsible for 2-/4-hydroxylation and 16α-hydroxylation of estradiol and estrone, steroids that can contribute to breast cancer risk. In contrast, CYP1A1 and CYP1B1 predominantly metabolized estrone and estradiol to 2- and 4-catechol estrogens, which are endogenous ultimate carcinogens if formed in the breast. Some metabolic activities of CYP3A4, including dehydroepiandrosterone 7β-/16α-hydroxylation, estrone 2-hydroxylation and testosterone 6β-hydroxylation, were higher than those for polymorphically expressed CYP3A5. Next, we considered typical steroidogenic P450s. CYP17A1, CYP19A1 and CYP27A1 catalyzed steroid synthesis, including hydroxylation at 17α, 19 and 27 positions, respectively. However, it was difficult to predict which hepatic drug-metabolizing P450 or steroidogenic P450 will be mainly responsible for metabolizing each steroid hormone in vivo based on these results. Further research is required on the metabolism of steroid hormones by various P450s and on prediction of their relative contributions to in vivo metabolism. The findings collected here provide fundamental and useful information on the metabolism of steroid compounds.
Topics: Adrenal Glands; Cholesterol; Cytochrome P-450 Enzyme System; Estradiol; Humans; Hydroxylation; In Vitro Techniques; Liver; Testosterone
PubMed: 25678418
DOI: 10.3109/03602532.2015.1011658 -
Journal of Personalized Medicine Jul 2023Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further.... (Review)
Review
Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for and , when there is an indication (side effects or inefficacy).
PubMed: 37511796
DOI: 10.3390/jpm13071183