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Inhibitor Ketoconazole (inhibitor + ketoconazole)
Selected AbstractsConversion of vitamin D3 to 1,,25-dihydroxyvitamin D3 in human skin equivalentsEXPERIMENTAL DERMATOLOGY, Issue 2 2000B. Lehmann Abstract: These results demonstrate for the first time that human keratinocytes under in vivo -like conditions have the capacity of the enzymatic hydroxylation of vitamin D3 to hormonally active calcitriol (1,,25(OH)2D3). Supplementation of the culture medium with bovine serum albumin (BSA) up to 1.5% (w/v) amplifies the conversion of vitamin D3 to 1,,25(OH)2D3. The maximum turnover rate of this reaction at 780 nM vitamin D3 in presence of 1.0% (w/v) BSA amounts to approximately 3 pmol 1,,25(OH)2D3 per 106 cells after 6 h of incubation. The hydroxylation of vitamin D3 to 1,,25(OH)2D3 is inhibited by the P-450 oxidase inhibitor ketoconazole. The generation of 1,,25(OH)2D3 from vitamin D3 has an apparent Michaelis constant (Km) of 2.3×10,6 M. The intrinsic conversion of vitamin D3 to biologically active 1,,25(OH)2D3 may be of importance for the regulation of proliferation and differentiation of keratinocytes. [source] Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1, mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiencyJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009J. C. COELHO P-glycoprotein (P-gp), the product of ABCB1 gene, is thought to play a role in the biliary excretion of a variety of drugs, but specific studies in dogs have not been performed. Because a number of endogenous (ABCB1 polymorphisms) and exogenous (pharmacological P-gp inhibition) factors can interfere with normal P-gp function, a better understanding of P-gp's role in biliary drug excretion is crucial in preventing adverse drug reactions and drug,drug interactions in dogs. The objectives of this study were to compare biliary excretion of technetium-99m-sestamibi (99mTc-MIBI), a radio-labelled P-gp substrate, in wild-type dogs (ABCB1 wild/wild), and dogs with intrinsic and extrinsic deficiencies in P-gp function. Dogs with intrinsic P-gp deficiency included ABCB1 mut/mut dogs, and dogs with presumed intermediate P-gp phenotype (ABCB1 mut/wild). Dogs with extrinsic P-gp deficiency were considered to be ABCB1 wild/wild dogs treated with the P-gp inhibitor ketoconazole (5 mg/kg PO q12h × 9 doses). Results from this study indicate that ABCB1 mut/mut dogs have significantly decreased biliary excretion of 99mTc-MIBI compared with ABCB1 wild/wild dogs. Treatment with ketoconazole significantly decreased biliary excretion of 99mTc-MIBI in ABCB1 wild/wild dogs. P-gp appears to play an important role in the biliary excretion of 99mTc-MIBI in dogs. It is likely that concurrent administration of a P-gp inhibitor such as ketoconazole will decrease P-gp-mediated biliary excretion of other substrate drugs as well. [source] Real time monitoring of drug metabolic enzyme response inside human hepatoma GS-3A4-HepG2 cells by means of electrochemical impedance measurementPOLYMERS FOR ADVANCED TECHNOLOGIES, Issue 5 2004Masaaki Kobayashi Abstract Cytochrome P-450s (CYPs) are important biopolymers for the maintenance of cellular function. If metabolic activity of the CYP in the cells can be estimated, so can the function of metabolism, which is closer to the organism. In this research, the method of measuring the drug metabolic activity inside the cell by making use of an electrochemical technique was examined. Human hepatoma GS-3A4-HepG2 cells of which the cytochrome P-4503A4 (CYP3A4) drug metabolic activity is found to be the same as that of primary hepatocytes were used in the experiment. The GS-3A4-HepG2 cells were cultured on an indium-tin oxide (ITO) electrode until they became confluent. Substrate testosterone and inhibitor ketoconazole of CYP3A4 were exposed to cells cultured on an ITO electrode, and the reaction was observed by noting the electrochemical impedance measurement. Impedance was decomposed into the resistance component and the reactance component, and each was examined in detail. As a result, according to testosterone concentration change, there was a remarkable time change in the reactance component. A similar impedance measurement was done by using human hepatoma HepG2 cells in which the drug metabolic activity had extremely decreased. Nevertheless, no time change in the reactance component that was noticed in GS-3A4-HepG2 cells was observed. Next, the amount of metabolite in the solution after impedance measurement was measured by means of liquid chromatography-tandem mass spectroscopy (LC-MS/MS). In the experiment with GS-3A4-HepG2 cells, a testosterone concentration-dependent correlation was observed between the reactance component change and the amount of metabolite. But, in the impedance measurement by ketoconazole, the change in reactance components was not observed in either the GS-3A4-HepG2 cells or the HepG2 cells. Ketoconazole and the heme iron in CYP3A4 effect the coordination bond, but ketoconazole was not metabolized by CYP3A4. It was confirmed that the time change in the reactance component which was caused by the testosterone was detected neither in the cells that take up the substrate, nor in the coordination bond between the CYP enzyme and the drug. Therefore, the time change in the remarkable reactance component observed by this electrochemical impedance measurement is dependent on drug metabolic activity. An electrochemical drug metabolic activity measuring method with the human hepatoma GS-3A4-HepG2 cells was able to be established. Copyright © 2004 John Wiley & Sons, Ltd. [source] Atmospheric pressure desorption/ionization on silicon ion trap mass spectrometry applied to the quantitation of midazolam in rat plasma and determination of midazolam 1,-hydroxylation kinetics in human liver microsomesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 24 2006Rick C. Steenwyk The application of atmospheric pressure desorption/ionization on silicon (AP-DIOS) coupled with ion trap mass spectrometry (ITMS) was investigated for the quantification of midazolam in rat plasma, and determination of midazolam 1,-hydroxylation kinetics in pooled human liver microsomes. Results indicate good sensitivity with absolute detection limits for midazolam in rat plasma of approximately 300 femtograms. A linear dynamic range from approximately 10,5000,ng/mL was obtained in rat plasma with analysis times of 1,min per sample. Kinetic constants for midazolam 1,-hydroxylation in human liver microsomes yielded an apparent Km of 10.0,µM and Vmax of 6.4,nmol/min/mg. Studies investigating the inhibition of 1,-hydroxymidazolam formation by the cytochrome P450 3A4 model inhibitor ketoconazole yielded an IC50 of 0.03,µM. Quantitative precision for replicate analysis of rat plasma and human liver microsomal samples was variable with relative standard deviation (RSD) values ranging from a low of approximately 3% to over 50%, with the highest variability observed in data from human liver microsomal incubations. While preliminary studies investigating the application of AP-DIOS-ITMS suggested feasibility of this technique to typical pharmacokinetic applications, further work is required to understand the underlying causes for the high variability observed in these investigations. Copyright © 2006 John Wiley & Sons, Ltd. [source] Contributions of human cytochrome P450 enzymes to glyburide metabolismBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2010Lin Zhou Abstract Glyburide (GLB) is a widely used oral sulfonylurea for the treatment of gestational diabetes. The therapeutic use of GLB is often complicated by a substantial inter-individual variability in the pharmacokinetics and pharmacodynamics of the drug in human populations, which might be caused by inter-individual variations in factors such as GLB metabolism. Therefore, there has been a continued interest in identifying human cytochrome P450 (CYP) isoforms that play a major role in the metabolism of GLB. However, contrasting data are available in the present literature in this regard. The present study systematically investigated the contributions of various human CYP isoforms (CYP3A4, CYP3A5, CYP2C8, CYP2C9 and CYP2C19) to in vitro metabolism of GLB. GLB depletion and metabolite formation in human liver microsomes were most significantly inhibited by the CYP3A inhibitor ketoconazole compared with the inhibitors of other CYP isoforms. Furthermore, multiple correlation analysis between GLB depletion and individual CYP activities was performed, demonstrating a significant correlation between GLB depletion and the CYP3A probe activity in 16 individual human liver microsomal preparations, but not between GLB depletion and the CYP2C19, CYP2C8 or CYP2C9 probe activity. By using recombinant supersomes overexpressing individual human CYP isoforms, it was found that GLB could be depleted by all the enzymes tested; however, the intrinsic clearance (Vmax/Km) of CYP3A4 for GLB depletion was 4,17 times greater than that of other CYP isoforms. These results confirm that human CYP3A4 is the major enzyme involved in the in vitro metabolism of GLB. Copyright © 2010 John Wiley & Sons, Ltd. [source] Everolimus drug interactions: application of a classification system for clinical decision makingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2006John M. Kovarik Abstract Introduction. More than half of all drugs used in medical practice are metabolized by cytochrome CYP3A. Coadministration of drugs that share this elimination pathway may lead to pharmacokinetic drug interactions. Efforts are underway by clinical, drug development and regulatory scientists to classify CYP3A-related drug interactions with the ultimate goal of improving guidance for clinical intervention. The CYP3A inhibitory classification system ranks inhibitors according to the fold-increase in area-under-the-curve (AUC) of a probe substrate as: strong (,5-fold), moderate (>2.0- to 4.9-fold), or weak (,2.0-fold). This classification system was applied to characterize everolimus as a CYP3A substrate. Methods. Five open-label crossover drug interaction studies were performed in 12,16 healthy subjects each. Subjects received a single 2 mg dose of everolimus alone and again during single- or multiple-dose treatment with the probe inhibitors ketoconazole, erythromycin, verapamil, cyclosporine and atorvastatin. Results. The fold-increase in everolimus AUC was: 15.0 with the strong inhibitor ketoconazole; 4.4, 3.5 and 2.7 with the moderate inhibitors erythromycin, verapamil and cyclosporine; and no change with the weak inhibitor atorvastatin. Subjects with low baseline AUCs when everolimus was given alone tended to have AUC increases of a higher magnitude (more potent interaction) in the presence of an inhibitor. Conclusions. Strong CYP3A inhibitors should be avoided when possible during everolimus treatment as compensatory everolimus dose reductions could be difficult to manage. Everolimus therapeutic drug monitoring should be used to guide individualized dose adjustments when moderate CYP3A inhibitors are added to or withdrawn from the regimen. Routine everolimus therapeutic drug monitoring should be sufficient to determine whether dose adjustments are needed when weak CYP3A inhibitors are coadministered. This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment. Copyright © 2006 John Wiley & Sons, Ltd. [source] Minimal effect of ketoconazole on cyclosporine (SangCyATM) oral absorption and first-pass metabolism in rats: evidence of a significant vehicle effect on SangCyA absorptionBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2002Susan Wong Abstract The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague,Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine Cmax (mean±SD 1.12±0.16 µg/ml) and AUC0,6 (5.34±0.71 µg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19±0.94 µg/ml and 9.52±2.52 µg h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however Tmax was unaffected. Ketoconazole increased cyclosporine Cmax and AUC0,6 by 50,60%, regardless of the vehicle or the cyclosporine dose, without altering Tmax (2,3 h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats. Copyright © 2002 John Wiley & Sons, Ltd. [source] Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumorsCANCER, Issue 6 2010Faye M. Johnson MD Abstract BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society. [source] Influence of quinidine, cimetidine, and ketoconazole on the enantioselective pharmacokinetics and metabolism of metoprolol in ratsCHIRALITY, Issue 10 2009Vanessa Bergamin Boralli Abstract Metoprolol is a ,-blocker and its racemic mixture is used for the treatment of hypertension. In the present study we investigated the influence of CYP2D and CYP3A on the stereoselective metabolism of metoprolol in rats. Male Wistar rats (n = 6 per group) received racemic metoprolol (15 mg/kg) orally, with or without pretreatment with the CYP inhibitor ketoconazole (50 mg/kg), cimetidine (150 mg/kg), or quinidine (80 mg/kg). Blood samples were collected up to 48 h after metoprolol administration. The plasma concentrations of the stereoisomers of metoprolol, O -demethylmetoprolol (ODM), ,-hydroxymetoprolol (OHM) (Chiralpak® AD column), and metoprolol acidic metabolite (AODM) (Chiralcel® OD-R column) were determined by HPLC using fluorescence detection (,exc = 229 nm; ,em = 298 nm). CYP3A inhibition by ketoconazole reduced the plasma concentrations of ODM and AODM and favored the formation of OHM. CYP2D and CYP3A inhibition by cimetidine reduced the plasma concentrations of OHM and AODM and favored the formation of ODM. The inhibition of CYP2D by quinidine reduced the plasma concentrations of OHM and favored the formation of ODM. In conclusion, the results suggest that CYP3A is involved in the formation of ODM and CYP2D is involved in the formation of AODM. Chirality 2009. © 2009 Wiley-Liss, Inc. [source] Everolimus drug interactions: application of a classification system for clinical decision makingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2006John M. Kovarik Abstract Introduction. More than half of all drugs used in medical practice are metabolized by cytochrome CYP3A. Coadministration of drugs that share this elimination pathway may lead to pharmacokinetic drug interactions. Efforts are underway by clinical, drug development and regulatory scientists to classify CYP3A-related drug interactions with the ultimate goal of improving guidance for clinical intervention. The CYP3A inhibitory classification system ranks inhibitors according to the fold-increase in area-under-the-curve (AUC) of a probe substrate as: strong (,5-fold), moderate (>2.0- to 4.9-fold), or weak (,2.0-fold). This classification system was applied to characterize everolimus as a CYP3A substrate. Methods. Five open-label crossover drug interaction studies were performed in 12,16 healthy subjects each. Subjects received a single 2 mg dose of everolimus alone and again during single- or multiple-dose treatment with the probe inhibitors ketoconazole, erythromycin, verapamil, cyclosporine and atorvastatin. Results. The fold-increase in everolimus AUC was: 15.0 with the strong inhibitor ketoconazole; 4.4, 3.5 and 2.7 with the moderate inhibitors erythromycin, verapamil and cyclosporine; and no change with the weak inhibitor atorvastatin. Subjects with low baseline AUCs when everolimus was given alone tended to have AUC increases of a higher magnitude (more potent interaction) in the presence of an inhibitor. Conclusions. Strong CYP3A inhibitors should be avoided when possible during everolimus treatment as compensatory everolimus dose reductions could be difficult to manage. Everolimus therapeutic drug monitoring should be used to guide individualized dose adjustments when moderate CYP3A inhibitors are added to or withdrawn from the regimen. Routine everolimus therapeutic drug monitoring should be sufficient to determine whether dose adjustments are needed when weak CYP3A inhibitors are coadministered. This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment. Copyright © 2006 John Wiley & Sons, Ltd. [source] | |||||||||||||