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Kidney International Sep 1998Heavy use of analgesics, particularly over-the-counter (OTC) products, has long been associated with chronic renal failure. Most of the earlier reports implicated... (Review)
Review
Heavy use of analgesics, particularly over-the-counter (OTC) products, has long been associated with chronic renal failure. Most of the earlier reports implicated phenacetin-containing analgesics as the risk factor. Since the early 1980s. several case-control studies have reported associations between chronic renal failure and use of other forms of analgesics, including acetaminophen, aspirin, and other non-steroidal antiinflammatory drugs (NSAIDs). Findings from these studies, however. should be interpreted with caution because of a number of inherent limitations and potential biases in the study design and data collection procedures. These limitations include: failure to identify patients early enough in the natural history of their disease to collect reliable information on analgesic use at an etiologically relevant time period; selection bias due to incomplete identification of subjects or low response rates; selection of cases and controls from different population bases; failure to employ survey techniques to improve reliability of recall of analgesic use; failure to collect detailed information on analgesic use such as year started and ended and reasons for switching analgesics; lack of standardization in the definition of regular analgesic use; and failure to adjust for phenacetin use and other confounding factors when assessing associations with analgesics other than those containing phenacetin. It is our hope that this review of study design limitations will lead to improvements in future studies of chronic renal failure risk. Since use of analgesics is widespread and new OTC products are introduced frequently, the potential impact of these drugs on the development of chronic renal failure may be significant, thus warranting continued evaluation of these products for any renal toxicity.
Topics: Analgesics; Case-Control Studies; Humans; Kidney Failure, Chronic
PubMed: 9734593
DOI: 10.1046/j.1523-1755.1998.00043.x -
Molecules (Basel, Switzerland) Oct 2023In this work, we present a comprehensive study of the thermodynamic properties of 3-and 4-ethoxyacetanilides. The heat capacities in crystalline, liquid, and supercooled...
In this work, we present a comprehensive study of the thermodynamic properties of 3-and 4-ethoxyacetanilides. The heat capacities in crystalline, liquid, and supercooled liquid states from 80 to 475 K were obtained using adiabatic, differential scanning (DSC), and fast scanning (FSC) calorimetries. The fusion enthalpies at were combined from DSC measurement results and the literature data. The fusion enthalpies at 298.15 K were evaluated in two independent ways: adjusted according to Kirchhoff's law of thermochemistry, and using Hess' law. For the latter approach, the enthalpies of the solution in DMF in crystalline and supercooled liquid states were derived. The values obtained by the two methods are consistent with each other. The standard thermodynamic functions (entropy, enthalpy, and Gibbs energy) between 80 and 470 K were calculated.
PubMed: 37894506
DOI: 10.3390/molecules28207027 -
Medical Science Monitor : International... May 2017BACKGROUND The risk of postoperative liver dysfunction (PLD) in patients with injured livers, such as in hepatocellular carcinoma (HCC), is still not negligible.... (Clinical Trial)
Clinical Trial
BACKGROUND The risk of postoperative liver dysfunction (PLD) in patients with injured livers, such as in hepatocellular carcinoma (HCC), is still not negligible. Phenacetin metabolism test can reflect hepatic functional reserve in patients with chronic hepatic damage. The aim of this study was to assess the ability of phenacetin metabolism test to predict PLD in patients with HCC receiving partial hepatectomy. MATERIAL AND METHODS Forty-nine patients with HCC undergoing partial hepatectomy between 2014 and 2016 were included at Huashan Hospital, Fudan University. The phenacetin metabolism test was used to assess the hepatic functional reserve. The ratio of total plasma paracetamol to phenacetin was collected in patients at 2 h after oral administration of 1.0 g phenacetin, recorded 5 days prior to surgery and on the fifth postoperative day. Phenacetin metabolism test, Child-Pugh classification, and Model for End-Stage Liver Disease (MELD) score were correlated with PLD. RESULTS Of 49 patients with HCC, 13 patients (26.5%) had PLD. The association between the ratio of total plasma paracetamol to phenacetin and PLD was statistically significant (p=0.0061) and the correlation coefficient was -0.647 (p=0.0082). The phenacetin metabolism test showed a larger area under the receiver operating characteristic (ROC) curve value (0.735) than Child-Pugh's classification (0.472) and MELD score (0.419). Using the calculated cutoff of 0.6, the lower ratio of total plasma paracetamol to phenacetin preoperatively was chosen to specifically identify patients with PLD. The sensitivity and specificity were 0.657 and 0.892, respectively. CONCLUSIONS Phenacetin metabolism test could be preoperatively used in predicting PLD in HCC patients receiving partial hepatectomy. It potentially provides better prediction than Child-Pugh classification and MELD score.
Topics: Carcinoma, Hepatocellular; Female; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Phenacetin; Postoperative Care; Preoperative Care
PubMed: 28553832
DOI: 10.12659/msm.905228 -
Pharmaceutics Feb 2022CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of...
CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin O-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. CYP1A2*1F, considered to be associated with high CYP1A2 inducibility, is generally identified by the presence of −163C>A polymorphism; however, we demonstrated that −163C>A existed in several haplotypes (CYP1A2*1F, CYP1A2*1L, CYP1A2*1M, CYP1A2*1V, CYP1A2*1W), and consequently, CYP1A2*1F was a much rarer allelic variant (0.4%) than reported in Caucasian populations. Of note, −163C>A polymorphism was found to result in an increase of neither mRNA nor the activity of CYP1A2. Moreover, hepatic CYP1A2 activity was associated with hepatic or leukocyte mRNA expression rather than genetic polymorphisms of CYP1A2. Consideration of non-genetic phenoconverting factors (co-medication with CYP1A2-specific inhibitors/inducers, tobacco smoking and non-specific factors, including amoxicillin+clavulanic acid therapy or chronic alcohol consumption) did not much improve genotype−phenotype estimation. In conclusion, CYP1A2-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity.
PubMed: 35335907
DOI: 10.3390/pharmaceutics14030532 -
Frontiers in Pharmacology 2020Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib...
Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The experiment was carried out by using rat liver microsomes (RLMs), whereas the experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration ( < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.
PubMed: 33746741
DOI: 10.3389/fphar.2020.593518 -
International Journal of Molecular... May 2018Leucine382 of cytochrome P450 1A2 (CYP1A2) plays an important role in binding and -dealkylation of phenacetin, with the L382V mutation increasing substrate oxidation...
Leucine382 of cytochrome P450 1A2 (CYP1A2) plays an important role in binding and -dealkylation of phenacetin, with the L382V mutation increasing substrate oxidation (Huang and Szklarz, 2010, . 38:1039⁻1045). This was attributed to altered substrate binding orientation, but no direct experimental evidence had been available. Therefore, in the current studies, we employed nuclear magnetic resonance (NMR) longitudinal (T₁) relaxation measurements to investigate phenacetin binding orientations within the active site of CYP1A2 wild type (WT) and mutants. Paramagnetic relaxation time (T) for each proton of phenacetin was calculated from the T₁ value obtained from the enzymes in ferric and ferrous-CO state in the presence of phenacetin, and used to model the orientation of phenacetin in the active site. All aromatic protons of phenacetin were nearly equidistant from the heme iron (6.34⁻8.03 Å). In contrast, the distance between the proton of the ⁻OCH₂⁻ group, which is abstracted during phenacetin oxidation, and the heme iron, was much shorter in the L382V (5.93 Å) and L382V/N312L (5.96 Å) mutants compared to the N312L mutant (7.84 Å) and the wild type enzyme (6.55 Å), consistent with modeling results. These studies provide direct evidence for the molecular mechanism underlying increased oxidation of phenacetin upon the L382V mutation.
Topics: Amino Acid Substitution; Catalytic Domain; Cloning, Molecular; Cytochrome P-450 CYP1A2; Escherichia coli; Gene Expression; Genetic Vectors; Humans; Kinetics; Models, Molecular; Mutation; Oxidation-Reduction; Phenacetin; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Recombinant Fusion Proteins; Substrate Specificity; Thermodynamics
PubMed: 29799514
DOI: 10.3390/ijms19061580 -
The Biochemical Journal Apr 19711. acetyl-(3)H- and ethyl-(14)C-labelled derivatives of phenacetin and related compounds are described. 2. Radioactive label from the ethyl-(14)C-labelled derivatives of...
1. acetyl-(3)H- and ethyl-(14)C-labelled derivatives of phenacetin and related compounds are described. 2. Radioactive label from the ethyl-(14)C-labelled derivatives of 4-nitrophenetole, 4-phenetidine and phenacetin binds in vitro to various extents to bovine plasma albumin, salmon sperm DNA and yeast RNA; the extent of binding is increased in the presence of a rat liver microsomal hydroxylating system and further increased when the microsomal enymes are induced by prior treatment of rats with 3-methylcholanthrene. 3. The ratios of the bound radioactive labels in vitro from [ethyl-(14)C]phenacetin, N-acetoxy[ethyl-(14)C]phenacetin, [acetyl-(3)H]phenacetin and [diacetyl-(3)H]N-acetoxyphenacetin per g-atom of DNA P, RNA P and per mol of protein in the absence of the microsomal system are approximately 1:60:11:863, 1:68:41:1835 and 1:88:713:2399 respectively. 4. Radioactive label from labelled phenacetin binds in vitro to all tissues examined, including the spleen, intestines, kidney and bladder; about 80% of the radioactivity bound to the liver is concentrated in the RNA and proteins. 5. Comparison of the relative extents of binding of radioactive label derived from equimolar amounts of labelled phenacetin, ethanol or acetate shows that the incorporation of labelled C(2) units into tissues and biological macromolecules in vivo and in vitro may account for only a part of the total bound radioactive label derived from phenacetin and not at all from the incorporation of radioactive acetate into nucleic acids. 6. Some implications of these findings are discussed.
Topics: Animals; Binding Sites; Carbon Isotopes; DNA; In Vitro Techniques; Intestinal Mucosa; Kidney; Liver; Male; Methylcholanthrene; Microsomes, Liver; Nucleic Acids; Phenacetin; Protein Binding; RNA; Rats; Serum Albumin, Bovine; Spleen; Tritium; Urinary Bladder
PubMed: 5118104
DOI: 10.1042/bj1220311 -
Acta Pharmacologica Sinica Apr 2004To study the effects of diphenytriazol on cytochrome P-450 (CYP) enzymes.
AIM
To study the effects of diphenytriazol on cytochrome P-450 (CYP) enzymes.
METHODS
SD rats were pretreated with diphenytriazol. The catalytic activities of rat liver microsomes were determined by assaying ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-dealkylase. Phenacetin and aminopyrine were selected as the substrate of CYP1A and CYP2B, respectively. The concentration of remaining substrate in microsomal incubates was determined by reversed-phase high-performance liquid chromatography (RP-HPLC). The inhibition of fluvoxamine or alpha-naphthoflavone on phenacetin metabolism was measured.
RESULTS
Phenacetin was significantly metabolized in the diphenytriazol-treated microsomes and the metabolic degree increased according to the diphenytriazol-treatment days. There existed a significant correlation between the metabolic degree of phenacetin and EROD in the microsomes pretreated with diphenytriazol. Both fluvoxamine and alpha-naphthoflavone inhibited the metabolism of phenacetin significantly, and the inhibition constants (K(i)) were (5.4+/-1.0) micromol/L and (10.4+/-0.5) micromol/L, respectively. The activity of microsomes pretreated with diphenytriazol for 4 d was similar to that in b-naphthoflavone group, but was significantly different from those in control group and phenobarbital group.
CONCLUSION
These results reveal that diphenytriazol is a novel inducer of CYP1A.
Topics: Abortifacient Agents, Nonsteroidal; Aminopyrine; Animals; Benzoflavones; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2B1; Female; Fluvoxamine; Microsomes, Liver; Phenacetin; Rats; Rats, Sprague-Dawley; Triazoles; beta-Naphthoflavone
PubMed: 15066225
DOI: No ID Found -
Journal of Advanced Research Jul 2022Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered...
INTRODUCTION
Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.
OBJECTIVES
In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.
METHODS
The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.
RESULTS
The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.
CONCLUSION
Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.
Topics: Animals; Chlorzoxazone; Gastrointestinal Microbiome; Metoprolol; Mice; Midazolam; Non-alcoholic Fatty Liver Disease; Omeprazole; Pharmaceutical Preparations; Phenacetin; Tolbutamide
PubMed: 35777915
DOI: 10.1016/j.jare.2021.10.004 -
Drug Metabolism and Disposition: the... Dec 2008Cytochrome P450s (P450s) metabolize a large number of diverse substrates with specific regio- and stereospecificity. A number of compounds, including nicotine, cotinine,...
Cytochrome P450s (P450s) metabolize a large number of diverse substrates with specific regio- and stereospecificity. A number of compounds, including nicotine, cotinine, and aflatoxin B(1), are metabolites of the 94% identical CYP2A13 and CYP2A6 enzymes but at different rates. Phenacetin and 4-aminobiphenyl were identified as substrates of human cytochromes P450 1A2 and 2A13 but not of CYP2A6. The purpose of this study was to identify active site amino acids that are responsible for CYP2A substrate specificity using phenacetin as a structural probe. Ten amino acid residues that differ in the CYP2A13 and CYP2A6 active sites were exchanged between the two enzymes. Phenacetin binding revealed that the six substitution, CYP2A13 S208I, A213S, F300I, A301G, M365V, and G369S decreased phenacetin affinity. Although incorporation of individual CYP2A13 residues into CYP2A6 had little effect on this enzyme's very low levels of phenacetin metabolism, the combination of double, triple, and quadruple substitutions at positions 208, 300, 301, and 369 increasingly endowed CYP2A6 with the ability to metabolize phenacetin. Enzyme kinetics revealed that the CYP2A6 I208S/I300F/G301A/S369G mutant protein O-deethylated phenacetin with a K(m) of 10.3 muM and a k(cat) of 2.9 min(-1), which compare very favorably with those of CYP2A13 (K(m) of 10.7 muM and k(cat) of 3.8 min(-1)). A 2.15 A crystal structure of the mutant CYP2A6 I208S/I300F/G301A/S369G protein with phenacetin in the active site provided a structural rationale for the differences in phenacetin metabolism between CYP2A6 and CYP2A13.
Topics: Amino Acid Substitution; Amino Acids; Aryl Hydrocarbon Hydroxylases; Catalysis; Catalytic Domain; Cytochrome P-450 CYP2A6; Humans; Kinetics; Models, Molecular; Molecular Conformation; Phenacetin; Protein Binding; Recombinant Proteins; Spectrophotometry; Steroid Hydroxylases; Substrate Specificity
PubMed: 18779312
DOI: 10.1124/dmd.108.023770