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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 -
Journal of Personalized Medicine Jul 2021Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of...
Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin -deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants.
PubMed: 34442334
DOI: 10.3390/jpm11080690 -
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 -
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 -
ACS Omega Oct 2019A new method of data interpretation based on classical nucleation theory is proposed in this work to elucidate the influence of solvents on the pre-exponential...
A new method of data interpretation based on classical nucleation theory is proposed in this work to elucidate the influence of solvents on the pre-exponential nucleation factor and interfacial energy using the induction time data for three crystallization systems, including isonicotinamide, lovastatin, and phenacetin. In this method, the pre-exponential nucleation factor is replaced by the intrinsic nucleation factor multiplied by temperature and divided by solution viscosity. The proposed method is applied to study the nucleation kinetics of isonicotinamide, lovastatin, and phenacetin among various solvents using the induction time data measured in this work. The results indicate that the intrinsic nucleation factor increases linearly with increasing square root of interfacial energy in various solvents for each system.
PubMed: 31656908
DOI: 10.1021/acsomega.9b02102