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Iranian Journal of Basic Medical... Apr 2018In this study, we aimed to evaluate the effect of salidroside on the activities of the different drug-metabolizing enzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4 in...
OBJECTIVES
In this study, we aimed to evaluate the effect of salidroside on the activities of the different drug-metabolizing enzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4 in rats, in which a specific probe drug was used for each enzyme.
MATERIALS AND METHODS
After pretreatment with salidroside, five probe drugs were simultaneously administered to rats by gavage. The given dose was 2.0 mg/kg for phenacetin (CYP1A2 activity), 4.0 mg/kg for bupropion (CYP2B6 activity), 2.0 mg/kg for losartan (CYP2C9 activity), 8.0 mg/kg for metoprolol (CYP2D6 activity) and 1.0 mg/kg for midazolam (CYP3A4 activity). Then, an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the concentrations of rats' blood, which were collected at different corresponding times.
RESULTS
Our data showed that salidroside exhibited an inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A4 activities by changing the main pharmacokinetic parameters (t1/2, CL/F, Cmax and AUC(0-∞)) of the four probe drugs in rats. However, no significant changes in CYP2D6 activity were observed.
CONCLUSION
In a word, the results displayed that salidroside could induce the activities of CYP1A2, CYP2B6, CYP2C9 and CYP3A4, which may influence the disposition of the drugs that are mainly metabolized by these pathways. Our research can provide the basis for the study of related herb-drug interactions in clinic.
PubMed: 29796228
DOI: 10.22038/IJBMS.2018.26106.6414 -
Journal of Pharmaceutical and... Jun 2018Corylin, an phenolic compound from Psoralea corylifolia, has been reported with various pharmacological properties but has poor bioavailability due to massive...
Corylin, an phenolic compound from Psoralea corylifolia, has been reported with various pharmacological properties but has poor bioavailability due to massive metabolism. In this study, twelve metabolites of corylin mainly involving in oxidation, hydration, glucuronidation and sulfation were detected in mice. Furthermore, the oxidation and hydration of corylin (M4) in human liver microsomes (HLM) and human intestine microsomes (HIM) were both efficient with high CL (intrinsic clearance) values of 24.29 and 42.85 μL/min/mg, respectively. CYP1A1, 1B1 and 2C19 contributed most for M4 with the CL values of 26.63, 33.09 and 132.41 μL/min/mg, respectively. Besides, M4 was strongly correlated with phenacetin-N-deacetylation (r = 0.885, p = 0.0001) and tolbutamide-4-oxidation (r = 0.727, p = 0.001) in twelve individual HLMs, respectively. In addition, corylin was efficiently glucuronidated (M7) in HLM (125.33 μL/min/mg) and in HIM (108.74 μL/min/mg). UGT1A1 contributed the most for M7 with the CL value of 122.32 μL/min/mg. Meanwhile, M7 was significantly correlated with β-estradiol-3-O-glucuronidation (r = 0.742, p = 0.006) in twelve individual HLMs. Moreover, the metabolism of corylin showed marked species differences. Taken together, corylin was subjected to massive first-pass metabolism in liver and intestine, while CYP1A1, 1B1, 2C19 and UGT1A1 were the main contributors. Finally, the proposed metabolic pathway of corylin involed CYP and UGT isoforms were summarized, which could help to understand the metabolic fate of corylin in vivo.
Topics: Animals; Cytochrome P-450 CYP1A1; Flavonoids; Glucuronides; Humans; Intestinal Mucosa; Kinetics; Liver; Male; Metabolomics; Mice; Microsomes, Liver; Phenols; Species Specificity
PubMed: 29631076
DOI: 10.1016/j.jpba.2018.03.047 -
BioMed Research International 2018Inhalation administration is a promising alternative to the invasive drug delivery methods. The particle size required for ideal drug aerosol preparation is between 1...
Inhalation administration is a promising alternative to the invasive drug delivery methods. The particle size required for ideal drug aerosol preparation is between 1 and 3 m. The application of microspherical particles of solid dispersions enhances bioavailability of poorly soluble drugs due to the solubilization. In the present work, the spray drying process of the production of microspherical particles of solid dispersions of polyvinylpyrrolidone K29-32 with model hydrophobic drug, phenacetin, was optimized using the results of DSC, PXRD, and viscometry. The diameter of the obtained particles is within 1-3 m range. The Gibbs energy of dissolution in water was shown to be negative for the mixture with polymer/phenacetin mass ratio 5 : 1. We have demonstrated that the optimal size distribution for the inhalation administration is obtained for microspherical particles produced using spray caps with 7.0 m hole size. The dissolution rates of phenacetin from the produced microspherical particles were faster than that of drug powder. As evidenced by powder X-ray diffraction data, phenacetin stayed in amorphous state for 4 months in microspherical particles of solid dispersions. According to the obtained results, strategic application of the spray drying process could be beneficial for the improvement of the pharmaceutical properties of model drug, phenacetin.
Topics: Administration, Inhalation; Aerosols; Calorimetry, Differential Scanning; Drug Compounding; Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Mass Spectrometry; Microspheres; Nanoparticles; Particle Size; Phenacetin; Povidone; Thermogravimetry; Water; X-Ray Diffraction
PubMed: 29546051
DOI: 10.1155/2018/2412156 -
BioMed Research International 2017The present study aimed to investigate the effect of anlotinib (AL3818) on pharmacokinetics of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C6, CYP2D1, CYP2D2, and...
The present study aimed to investigate the effect of anlotinib (AL3818) on pharmacokinetics of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C6, CYP2D1, CYP2D2, and CYP3A1/2) by using five cocktail probe drugs in vivo. After pretreatment for 7 days with anlotinib (treatment group) or saline (control group) by oral administration, probe drugs phenacetin, tolbutamide, omeprazole, metoprolol, and midazolam were administered to rats by oral administration. Blood samples were obtained at a series of time-points and the concentrations of five probe drugs in plasma were determined by a UHPLC-MS/MS method. The results showed that treatment with anlotinib had no significant effect on rat CYP1A2, CYP2D2, and CYP2C6. However, anlotinib had a significant inductive effect on CYP2D1 and CYP3A1/2. Therefore, caution is needed during the concomitant use of anlotinib with other drugs metabolized by CYP2D1 and CYP3A1/2 because of potential drug-anlotinib interactions.
Topics: Animals; Antineoplastic Agents; Cytochrome P-450 Enzyme System; Drug Interactions; Indoles; Male; Quinolines; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry
PubMed: 29441353
DOI: 10.1155/2017/3619723 -
Clinical and Applied... Sep 2018Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow... (Clinical Trial)
Clinical Trial
Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450. High CYP 450 activity may lead to low drug concentration and requires high warfarin doses to reach efficacy; conversely, low CYP 450 activity is responsible for high drug concentration and needs for low doses to avoid potential toxicity risks. The major isoforms of CYP involved in the metabolism of warfarin sodium are CYP1A2 (for the R-warfarin) and CYP2C9 (for the S-warfarin). The probes for testing CYP1A2 are phenacetin and caffeine while for CYP2C9 tolbutamide. Although S-warfarin has major activity, it was decided to exclude its phenotyping for ethical issues, being mandatory to use a drug (tolbutamide). Instead, it was chosen to test the 1A2 isoform, as the activity of the latter isoform could be investigated by using caffeine contained in the caffeinated beverages. Specifically, a single-point concentration of salivary caffeine (total overnight salivary caffeine assessment [TOSCA]) after an overnight period of the caffeinated beverages abstinence was utilized. In the present study, 75 nonsmoker patients regularly receiving warfarin sodium were enrolled. The results have showed a significant association of the warfarin dose with TOSCA values (coefficient = -0.15, standard error = 0.04, 95% confidence interval = -0.24 to -0.06, t = -3.23, P = .002). In conclusion, the phenotyping of CYP1A2 by TOSCA could be useful, if further proven, to help manage patients on warfarin in order to lessen severe adverse events.
Topics: Adult; Aged; Aged, 80 and over; Caffeine; Cross-Sectional Studies; Cytochrome P-450 CYP1A2; Female; Humans; International Normalized Ratio; Isoenzymes; Male; Middle Aged; Phenazines; Saliva; Warfarin
PubMed: 28992765
DOI: 10.1177/1076029617733040 -
Talanta Jan 2018An office paper-based colorimetric device is proposed as a portable, rapid, and low-cost sensor for forensic applications aiming to detect phenacetin used as adulterant...
An office paper-based colorimetric device is proposed as a portable, rapid, and low-cost sensor for forensic applications aiming to detect phenacetin used as adulterant in illicit seized materials such as cocaine. The proposed method uses white office paper as the substrate and wax printing technology to fabricate the detection zones. Based on the optimum conditions, a linear analytical curve was obtained for phenacetin concentrations ranging from 0 to 64.52µgmL, and the straight line was in accordance with the following equation: (Magenta percentage color) = 1.19 + 0.458 (C/µgmL), R = 0.990. The limit of detection was calculated as 3.5µgmL (3σ/slope). The accuracy of the proposed method was evaluated using real seized cocaine samples and the spike-recovery procedure.
Topics: Cocaine; Colorimetry; Costs and Cost Analysis; Drug Contamination; Naphthoquinones; Paper; Phenacetin; Printing; Waxes
PubMed: 28917806
DOI: 10.1016/j.talanta.2017.08.082 -
BioMed Research International 2017Formaldehyde (FA) is an occupational and indoor pollutant. Long-term exposure to FA can irritate the respiratory mucosa, with potential carcinogenic effects on the...
Formaldehyde (FA) is an occupational and indoor pollutant. Long-term exposure to FA can irritate the respiratory mucosa, with potential carcinogenic effects on the airways. The effects of acute FA poisoning on the activities of CYP450 isoforms CYP1A2, CYP2C11, CYP2E1, and CYP3A2 were assessed by determining changes in the pharmacokinetic parameters of the probe drugs phenacetin, tolbutamide, chlorzoxazone, and testosterone, respectively. Rats were randomly divided into three groups: control, low FA dose (exposure to 110 ppm for 2 h for 3 days), and high FA dose (exposure to 220 ppm for 2 h for 3 days). A mixture of the four probe drugs was injected into rats and blood samples were taken at a series of time points. Plasma concentrations of the probe drugs were measured by HPLC. The pharmacokinetic parameters , AUC, and of tolbutamide, chlorzoxazone, and testosterone increased significantly in the high dose versus control group ( < 0.05), whereas the CL of chlorzoxazone and testosterone decreased significantly ( < 0.05). However, , AUC, and of phenacetin decreased significantly ( < 0.05), whereas the CL of phenacetin increased significantly ( < 0.05) compared to controls. Thus, acute FA poisoning suppressed the activities of CYP2C11, CYP2E1, and CYP3A2 and induced the activity of CYP1A2 in rats. And the change of CYP450 activity caused by acute FA poisoning may be associated with FA potential carcinogenic effects on the airways.
Topics: Air Pollutants; Animals; Chlorzoxazone; Cytochrome P-450 Enzyme System; Formaldehyde; Isoenzymes; Male; Rats; Rats, Sprague-Dawley; Testosterone; Tolbutamide
PubMed: 28555194
DOI: 10.1155/2017/6525474 -
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 -
International Journal of Molecular... May 2017Magnolin, epimagnolin A, dimethyllirioresinol, eudesmin, and fargesin are pharmacologically active tetrahydrofurofuranoid lignans found in Flos Magnoliae. The inhibitory...
Magnolin, epimagnolin A, dimethyllirioresinol, eudesmin, and fargesin are pharmacologically active tetrahydrofurofuranoid lignans found in Flos Magnoliae. The inhibitory potentials of dimethyllirioresinol, epimagnolin A, eudesmin, fargesin, and magnolin on eight major human cytochrome P450 (CYP) enzyme activities in human liver microsomes were evaluated using liquid chromatography-tandem mass spectrometry to determine the inhibition mechanisms and inhibition potency. Fargesin inhibited CYP2C9-catalyzed diclofenac 4'-hydroxylation with a Ki value of 16.3 μM, and it exhibited mechanism-based inhibition of CYP2C19-catalyzed [S]-mephenytoin 4'-hydroxylation (Ki, 3.7 μM; kinact, 0.102 min-1), CYP2C8-catalyzed amodiaquine N-deethylation (Ki, 10.7 μM; kinact, 0.082 min-1), and CYP3A4-catalyzed midazolam 1'-hydroxylation (Ki, 23.0 μM; kinact, 0.050 min-1) in human liver microsomes. Fargesin negligibly inhibited CYP1A2-catalyzed phenacetin O-deethylation, CYP2A6-catalyzed coumarin 7-hydroxylation, CYP2B6-catalyzed bupropion hydroxylation, and CYP2D6-catalyzed bufuralol 1'-hydroxylation at 100 μM in human liver microsomes. Dimethyllirioresinol weakly inhibited CYP2C19 and CYP2C8 with IC50 values of 55.1 and 85.0 μM, respectively, without inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, and CYP3A4 activities at 100 μM. Epimagnolin A, eudesmin, and magnolin showed no the reversible and time-dependent inhibition of eight major CYP activities at 100 μM in human liver microsomes. These in vitro results suggest that it is necessary to investigate the potentials of in vivo fargesin-drug interaction with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates.
Topics: Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Furans; Humans; Lignans; Microsomes, Liver
PubMed: 28468305
DOI: 10.3390/ijms18050952 -
Drug Metabolism and Disposition: the... May 2017MicroRNAs (miRNAs or miRs), including miR-34a, have been shown to regulate nuclear receptor, drug-metabolizing enzyme, and transporter gene expression in various cell...
MicroRNAs (miRNAs or miRs), including miR-34a, have been shown to regulate nuclear receptor, drug-metabolizing enzyme, and transporter gene expression in various cell model systems. However, to what degree miRNAs affect pharmacokinetics (PK) at the systemic level remains unknown. In addition, miR-34a replacement therapy represents a new cancer treatment strategy, although it is unknown whether miR-34a therapeutic agents could elicit any drug-drug interactions. To address this question, we refined a practical single-mouse PK approach and investigated the effects of a bioengineered miR-34a agent on the PK of several cytochrome P450 probe drugs (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail. This approach involves manual serial blood microsampling from a single mouse and requires a sensitive liquid chromatography-tandem mass spectrometry assay, which was able to illustrate the sharp changes in midazolam PK by ketoconazole and pregnenolone 16-carbonitrile as well as phenacetin PK by -naphthoflavone and 3-methylcholanthrene. Surprisingly, 3-methylcholanthrene also decreased systemic exposure to midazolam, whereas both pregnenolone 16-carbonitrile and 3-methylcholanthrene largely reduced the exposure to dextromethorphan, diclofenac, and chlorzoxazone. Finally, the biologic miR-34a agent had no significant effects on the PK of cocktail drugs but caused a marginal (45%-48%) increase in systemic exposure to midazolam, phenacetin, and dextromethorphan in mice. In vitro validation of these data suggested that miR-34a slightly attenuated intrinsic clearance of dextromethorphan. These findings from single-mouse PK and corresponding mouse liver microsome models suggest that miR-34a might have minor or no effects on the PK of coadministered cytochrome P450-metabolized drugs.
Topics: Animals; Chlorzoxazone; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dextromethorphan; Diclofenac; Drug Interactions; Male; Mice; MicroRNAs; Midazolam; Pharmacokinetics; Phenacetin
PubMed: 28254952
DOI: 10.1124/dmd.116.074344