-
IUCrData Aug 2020In the title compound, CHNO, the torsion angles about the bonds to the benzene ring are less than 4°, except for the nitro groups, which are twisted out of the ring...
In the title compound, CHNO, the torsion angles about the bonds to the benzene ring are less than 4°, except for the nitro groups, which are twisted out of the ring plane by 25.27 (3) and 43.63 (2)°. The N-H group forms a bifurcated hydrogen bond, with an intra-molecular component to a nitro group O atom and an inter-molecular component to the other nitro group, thereby forming chains propagating in the [010] direction. Several weak C-H⋯O inter-actions are also present.
PubMed: 36338512
DOI: 10.1107/S2414314620011219 -
The Journal of International Medical... Aug 2020This study was performed to examine the treatment regimen used for an elderly patient with diffuse large B-cell lymphoma (DLBCL) complicated with renal dysfunction.
OBJECTIVE
This study was performed to examine the treatment regimen used for an elderly patient with diffuse large B-cell lymphoma (DLBCL) complicated with renal dysfunction.
CASE REPORT
An 85-year-old man presented with nasal and sinus disorders in May 2018. He was also found to have renal insufficiency caused by long-term consumption of compound aminopyrine phenacetin tablets. Physical examination revealed irritation of the nasal mucous membrane on the right side and dark red nasal passages with a smooth surface. The right side of the neck contained several small peanut-sized lymph nodes. A biopsy of the right nasal neoplasm revealed germinal center type DLBCL. The mini-rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (mini-R-CHOP) was administered as the main chemotherapy regimen. Additionally, the use of thrombopoietin prevented further deterioration in renal function. This individualized treatment program helped the patient to achieve complete remission. The creatinine level decreased and was well maintained.
CONCLUSION
The mini-R-CHOP and rituximab cross-use regimen was found to be safe in an elderly patient with chronic renal insufficiency. Thrombopoietin exerted a protective effect on renal function.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Humans; Kidney Diseases; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Prednisone; Vincristine
PubMed: 32787736
DOI: 10.1177/0300060520945858 -
Chemico-biological Interactions Sep 2020Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate...
Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate the effects of acacetin on the activities of the cytochrome P450 family members CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1, and CYP3A2 in rat liver microsomes in vitro and rats in vivo to evaluate potential herb-drug interactions by using a cocktail approach. Phenacetin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and midazolam were chosen as the probe substrates. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous detection of the probe substrates and their metabolites. In vitro, the mode of acacetin inhibition of CYP2B1, CYP2C11, and CYP2E1 was competitive, while mixed inhibition was observed for CYP1A2 and CYP3A2. The Ki values in this study were less than 8.32 μM. In vivo, the mixed probe substrates were administered by gavage after daily intraperitoneal injection with 50 mg/kg acacetin or saline for 2 weeks. The main pharmacokinetic parameters, area under the plasma concentration-time curve (AUC), plasma clearance (CL), and maximum plasma concentration (C) of the probe substrates were significantly different in the experimental group than in the control group. Overall, the in vitro and in vivo results indicated that acacetin would be at high risk to cause toxicity and drug interactions via cytochrome P450 inhibition.
Topics: Animals; Area Under Curve; Cytochrome P-450 Enzyme System; Flavones; Half-Life; Inhibitory Concentration 50; Kinetics; Male; Microsomes, Liver; ROC Curve; Rats; Rats, Sprague-Dawley
PubMed: 32738202
DOI: 10.1016/j.cbi.2020.109147 -
Scientific Reports Jun 2020High-performance liquid chromatography (HPLC) is the most common analytical method practiced in various fields and used for analysis of almost all drug compounds in the... (Comparative Study)
Comparative Study
High-performance liquid chromatography (HPLC) is the most common analytical method practiced in various fields and used for analysis of almost all drug compounds in the pharmaceutical industries. During drug development, an evaluation of potential drug interaction with cytochrome P450 (CYP) is essential. A "cocktail" approach is often used in drug development to evaluate the effect of a drug candidate on multiple CYP enzymes in a single experiment. So far, simultaneous analysis of multiple CYP substrates, which have greatly different structure and physicochemical properties, has required organic solvents and mobile phase gradient methods. However, despite the recent emphasis on environmental protection, analytical methods that use only aqueous solvents without the use of organic solvents for separation have not been studied well. This study sought to develop the simultaneous analysis of multiple CYP substrates by using poly(N-isopropylacrylamide) (PNIPAAm)-based temperature-responsive chromatography with only aqueous solvents and isocratic methods. Good separation of multiple CYP substrates was achieved without using organic solvents and any gradient methods by temperature-responsive chromatography utilizing a P(NIPAAm-co-n-butyl methacrylate (BMA))- and P(NIPAAm-co-N-acryloyl L-tryptophan methyl ester (L-Trp-OMe))-grafted silica column. Overall, PNIPAAm-based temperature-responsive chromatography represents a remarkably simple, versatile, and environmentally friendly bioanalytical method for CYP substrates and their metabolites.
Topics: Acrylic Resins; Chlorzoxazone; Chromatography, Liquid; Coumarins; Cytochrome P-450 Enzyme System; Drug Development; Green Chemistry Technology; Mephenytoin; Molecular Structure; Phenacetin; Solvents; Substrate Specificity; Temperature; Testosterone; Tolbutamide; Water
PubMed: 32483226
DOI: 10.1038/s41598-020-65270-z -
Evidence-based Complementary and... 2020Red ginseng is often combined with to reduce alkaloids-related toxicity of the latter. Such herb-pairing also results in better therapeutic effect in heart failure, as...
Red ginseng is often combined with to reduce alkaloids-related toxicity of the latter. Such herb-pairing also results in better therapeutic effect in heart failure, as compared to the singular use of either herb. The purpose of this study was to investigate the effect of and its combination with red ginseng on the activities of CYP450 enzymes in rats. A sensitive and reliable HPLC-MS/MS method was established and validated for the simultaneous determination of eight probe drugs, phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), dapsone (CYP3A4), 7-hydroxycoumarin (CYP2A6), bupropion (CYP2B6), and amodiaquine (CYP2C8), in rat plasma using diazepam as internal standard (IS). The chromatographic separation was performed on a Waters XBridge™ C18 column (2.1 mm × 100 mm, 3.5 m) using a gradient elution with the mobile phase consisting of acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. The method was successfully applied in evaluating the effect of and red ginseng on the activities of CYP450 enzymes. The pharmacokinetic results of the eight probe drugs suggested that may inhibit the activity of CYP2A6, CYP2C19, CYP2B6, CYP1A2, CYP3A4, and CYP2C9 enzymes in rats. Comparison between the two groups, combined with red ginseng and , indicated that red ginseng may inhibit the activity of CYP2D6 and CYP2B6 enzymes while inducing the activity of CYP1A2, CYP3A4, and CYP2C9 enzymes.
PubMed: 32215046
DOI: 10.1155/2020/8603934 -
Pharmaceutics Mar 2020Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody-drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine...
Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody-drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5'-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug-drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine -β-d-glucuronidation, with values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25-2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC values of 93.7 109.1, 36.8 18.3, 160.6 167.4, 32.1 14.9, 578.4 452.0, 539.5 233.4, 856.7 781.9, and 54.1 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin -deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.
PubMed: 32131538
DOI: 10.3390/pharmaceutics12030220 -
RSC Advances Mar 2020PI-103 is a phosphatidylinositol 3-kinase inhibitor that includes multiple receptor affinity modifications, and it is also a therapeutic drug candidate primarily for...
An investigation of the metabolic activity, isozyme contribution, species differences and potential drug-drug interactions of PI-103, and the identification of efflux transporters for PI-103--glucuronide in HeLa1A9 cells.
PI-103 is a phosphatidylinositol 3-kinase inhibitor that includes multiple receptor affinity modifications, and it is also a therapeutic drug candidate primarily for human malignant tumors. However, its metabolic fate and potential drug-drug interactions involving human cytochrome P450 (CYP) and UDP-glucuronosyltransferases (UGT) enzymes remain unknown. In this study, our results demonstrated that the intrinsic clearance (CL) values of oxidated metabolite (M1) in human liver microsomes (HLM) and human intestine microsomes (HIM) were 3.10 and 0.08 μL min mg, respectively, while PI-103 underwent efficient glucuronidation with CL values of 15.59 and 211.04 μL min mg for mono-glucuronide (M2) by HLM and HIM, respectively. Additionally, reaction phenotyping results indicated that CYP1A1 (51.50 μL min mg), 1A2 (46.96 μL min mg), and UGT1A1 (18.80 μL min mg), 1A7 (8.52 μL min mg), 1A8 (8.38 μL min mg), 1A9 (34.62 μL min mg), 1A10 (107.01 μL min mg) were the most important contributors for the oxidation and glucuronidation of PI-103. Chemical inhibition assays also suggest that CYP1A2 and UGT1A1, 1A9 play a predominant role in the metabolism of PI-103 in HLM. Significant activity correlations were detected between phenacetin--deacetylation and M1 ( = 0.760, = 0.004) as well as β-estradiol-3--glucuronide and M2 ( = 0.589, = 0.044), and propofol--glucuronidation and M2 ( = 0.717, = 0.009). Furthermore, the metabolism of PI-103 revealed marked species differences, and dogs, rats, mice and mini-pigs were not the appropriate animal models. Gene silencing of breast cancer resistance protein (BCRP) or multidrug resistance-associated protein (MRPs) transporter results indicated that M2 was mainly excreted by BCRP, MRP1 and MRP4 transporters. Moreover, PI-103 displayed broad-spectrum inhibition towards human CYPs and UGTs isozymes with IC values ranging from 0.33 to 6.89 μM. Among them, PI-103 showed potent non-competitive inhibitory effects against CYP1A2, 2C19, 2E1 with IC and values of less than 1 μM. In addition, PI-103 exhibited moderate non-competitive inhibition against UGT1A7, 2B7, and moderate mixed-type inhibition towards CYP2B6, 2C9 and UGT1A3. Their IC and values were 1.16-6.89 and 0.56-5.64 μM, respectively. In contrast, PI-103 could activate the activity of UGT1A4 in a mechanistic two-site model with a value of 13.76 μM. Taken together, PI-103 was subjected to significant hepatic and intestinal metabolism. CYP1A1, 1A2 and UGT1A1, 1A7, 1A8, 1A9, 1A10 were the main contributing isozymes, whereas BCRP, MRP1 and MRP4 contributed most to the efflux excretion of M2. Meanwhile, PI-103 had a potent and broad-spectrum inhibitory effect against human CYPs and UGTs isozymes. These findings could improve understanding of the metabolic fates and efflux transport of PI-103. The inhibited human CYP and UGT activities could trigger harmful DDIs when PI-103 is co-administered with clinical drugs primarily cleared by these CYPs or UGTs isoforms. Additional studies are required to evaluate the clinical significance of the data presented herein.
PubMed: 35497201
DOI: 10.1039/c9ra09906a -
Frontiers in Pharmacology 2020Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to...
BACKGROUND
Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to proton-pump inhibitors, the determination of the drug-drug interactions is vital for further applications. Probe drug cocktails are a type of rapid, economical, and efficient approach for evaluating cytochrome P450 enzyme activities. Since vonoprazan is metabolized partly by cytochrome P450, cocktails were used to study CYP-based drug-drug interactions.
METHODS
This study was conducted both and . In the study of rat liver microsomes, ultra-performance liquid chromatography coupled to tandem mass spectrometry was utilized to assess the reversible inhibition of cytochrome P450 by vonoprazan by determining the concentration of probe drugs (phenacetin, bupropion, tolbutamide, dextromethorphan, midazolam, chlorzoxazone). The differences in the levels of probe drugs between the rat groups with or without vonoprazan administration were also tested in the rats.
RESULTS
analysis revealed that the IC values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 μM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant ( < 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different.
CONCLUSION
The and results indicated that vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6, suggesting that the coadministration of vonoprazan with cytochrome P450 substrates should be performed cautiously in clinical settings.
PubMed: 32116727
DOI: 10.3389/fphar.2020.00053 -
Drug Design, Development and Therapy 2020Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic...
BACKGROUND
Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases.
AIM
The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism.
METHODS
Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).
RESULTS
No significant differences were observed for omeprazole and midazolam, compared to the control group. and t values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group ( h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, <0.001).
CONCLUSION
Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.
Topics: Animals; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drugs, Chinese Herbal; Isoflavones; Medicine, Chinese Traditional; Metoprolol; Midazolam; Omeprazole; Phenacetin; Rats; Tolbutamide
PubMed: 32099327
DOI: 10.2147/DDDT.S236221 -
Molecules (Basel, Switzerland) Nov 2019The inhibitory effect of new chemical entities on rat liver P450 marker activities was investigated in a functional approach towards drug development. Treatment of...
Validation of an HPLC Method for the Simultaneous Quantification of Metabolic Reaction Products Catalysed by CYP2C11 Enzymes in Rat Liver Microsomes: In Vitro Inhibitory Effect of Salicylic Acid on CYP2C11 Enzyme.
The inhibitory effect of new chemical entities on rat liver P450 marker activities was investigated in a functional approach towards drug development. Treatment of colorectal cancer (CRC) and chemoprevention using salicylic acid has gained a lot of attention, mainly in the prevention of the onset of colon cancer. Thus, an in vitro inhibitory effect of salicylic acid on rat CYP2C11 activity was examined by using high performance liquid chromatography (HPLC). High performance liquid chromatography analysis of a CYP2C11 assay was developed on a reversed phase C column (SUPELCO 25 cm × 4.6 mm × 5 µm) at 243 nm using 32% phosphate buffer (pH 3.36) and 68% methanol as a mobile phase. The CYP2C11 assay showed good linearity for all components (R > 0.999). Substrates and metabolites were found to be stable for up to 72 hours. Additionally, the method demonstrated good reproducibility, intra- and inter-day precision (<15%), acceptable recovery and accuracy (80%-120%), and low detection (1.3501 µM and 3.2757 µM) and quantitation limit values (4.914 µM and 9.927 µM) for 16α-hydroxytestosterone and testosterone, respectively. Salicylic acid acts reversibly as a noncompetitive (weak) inhibitor with K = 84.582 ± 2.67 µM (concentration of inhibitor to cause 50% inhibition of original enzyme activity (IC) = 82.70 ± 2.67 µM) for CYP2C11 enzyme activity. This indicates a low potential to cause toxicity and drug-drug interactions.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Catalysis; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P450 Family 2; Drug Development; Humans; Liver; Rats; Salicylic Acid; Steroid 16-alpha-Hydroxylase
PubMed: 31775347
DOI: 10.3390/molecules24234294