The Experts below are selected from a list of 6465 Experts worldwide ranked by ideXlab platform
Leslie Z. Benet - One of the best experts on this subject based on the ideXlab platform.
-
in vitro evaluation of the disposition of a novel Cysteine Protease Inhibitor
Drug Metabolism and Disposition, 2000Co-Authors: Wolfgang Jacobsen, Uwe Christians, Leslie Z. BenetAbstract:K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl) is a potent, irreversible Cysteine Protease Inhibitor. Its therapeutic targets are cruzain, a Cysteine Protease of the protozoan parasiteTrypanosoma cruzi, and cathepsins B and L, which are associated with cancer progression. We evaluated the metabolism of K11777 by human liver microsomes, isolated cytochrome P450 (CYP) enzymes, and flavin-containing monooxygenase 3 (FMO3) in vitro. K11777 was metabolized by human liver microsomes to three major metabolites:N-oxide K11777 (apparentKm = 14.0 ± 4.5 μM and apparentVmax = 3460 ± 3190 pmol · mg−1 · min−1, n = 4), β-hydroxy-homoPhe K11777 (Km = 16.8 ± 3.5 μM and Vmax = 1260 ± 1090 pmol · mg−1 · min−1, n = 4), andN-desmethyl K11777 (Km = 18.3 ± 7.0 μM and Vmax = 2070 ± 1830 pmol · mg−1 · min−1, n = 4). All three K11777 metabolites were formed by isolated CYP3A and their formation by human liver microsomes was inhibited by the CYP3A Inhibitor cyclosporine (50 μM, 54–62% inhibition) and antibodies against human CYP3A4/5 (100 μg of antibodies/100 μg microsomal protein, 55–68% inhibition). CYP2D6 metabolized K11777 to its N-desmethyl metabolite with an apparent Km (9.2 ± 1.4 μM) lower than for CYP3A4 (25.0 ± 4.0 μM) and human liver microsomes. The apparent Km forN-oxide K11777 formation by cDNA-expressed FMO3 was 109 ± 11 μM. Based on the intrinsic formation clearances and the results of inhibition experiments (CYP2D6, 50 μM bufuralol; FMO3 mediated, 100 mM methionine) using human liver microsomes, it was estimated that CYP3A contributes to >80% of K11777 metabolite formation. K11777 was a potent (IC50 = 0.06 μM) and efficacious (maximum inhibition 85%) NADPH-dependent Inhibitor of human CYP3A4 mediated 6′β-hydroxy lovastatin formation, suggesting that K11777 is not only a substrate but also a mechanism-based Inhibitor of CYP3A4.
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8–10 wk old, n = 3–6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 ± 4.4 to 102 ± 24 mg · min/liter and decreased K02 oral plasma clearance from 3810 ± 1620 to 306 ± 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 ± 17 to 107 ± 14 mg · min/liter) and clearance (from 110 ± 22 to 95 ± 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 ± 1.4 to 31.0 ± 7.5% (P
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T Lin, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8-10 wk old, n = 3-6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 +/- 4.4 to 102 +/- 24 mg . min/liter and decreased K02 oral plasma clearance from 3810 +/- 1620 to 306 +/- 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 +/- 17 to 107 +/- 14 mg . min/liter) and clearance (from 110 +/- 22 to 95 +/- 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 +/- 1.4 to 31.0 +/- 7.5% (P < .001). In summary, ketoconazole, a dual Inhibitor of CYP3A and P-glycoprotein, can effectively increase K02 oral bioavailability by inhibiting the CYP3A/P-gp absorption barrier in the small intestine.
-
overlapping substrate specificities of cytochrome p450 3a and p glycoprotein for a novel Cysteine Protease Inhibitor
Drug Metabolism and Disposition, 1998Co-Authors: Yuanchao Zhang, Leslie Z. BenetAbstract:K02 (morpholine-urea-Phe-Hphe-vinylsulfone), a newly developed peptidomimetic, acts as a potent Cysteine Protease Inhibitor, especially of cathepsins B and L (which are associated with cancer progression) and cruzain (a Cysteine Protease of Trypanosoma cruzi , which is responsible for Chagas’ disease). Here we investigated features of the disposition of K02 using in vitro systems, characterizing the interaction of the drug with human cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), a mediator of multidrug resistance (MDR) to cancer chemotherapy and a countertransporter in the intestine that limits oral drug bioavailability. P-gp functions as an ATP-dependent drug efflux pump to reduce intracellular cytotoxic concentrations. An HPLC assay was developed to analyze K02 and its metabolites formed in human liver microsomes. Three major primary metabolites were determined by LC/MS/MS to be hydroxylated products of the parent compound. A rabbit anti-CYP3A polyclonal antibody (200 μl antibody/mg microsomal protein) produced 75–94% inhibition of the formation of these three hydroxylated metabolites. Ketoconazole (5 μM), a selective CYP3A Inhibitor, produced up to 75% inhibition, whereas other CYP-specific Inhibitors, i.e. quinidine (CYP2D6), 7,8-benzoflavone (CYP1A2), and sulfaphenazole (CYP2C9), showed no significant effects. An identical metabolite formation profile for K02 was observed with cDNA-expressed human CYP3A4 (Gentest). These data demonstrate that K02 is a substrate for CYP3A. Formation of 1′-hydroxymidazolam, the primary human midazolam metabolite, was markedly inhibited by K02 via competitive processes, which suggests the potential for drug-drug interactions of K02 with other CYP3A substrates. K02 significantly inhibited the photoaffinity labeling of P-gp with azidopine and LU-49888, a photoaffinity analogue of verapamil. Transport studies with [ 14 C]K02, using MDR1 -transfected Madin-Darby canine kidney cell monolayers in the Transwell system, demonstrated that the basolateral-to-apical flux of K02 across MDR1 -transfected Madin-Darby canine kidney cells was markedly greater than the apical-to-basolateral flux (ratio of 63 with 10 μM [ 14 C]K02). This suggests that K02 is also a P-gp substrate. These studies are important for formulating strategies to increase the absorption and/or decrease the elimination of K02 and to optimize its delivery to malignant cells and parasite-infected host cells.
-
Characterization of P-glycoprotein Mediated Transport of K02, a Novel Vinylsulfone Peptidomimetic Cysteine Protease Inhibitor, Across MDR1-MDCK and Caco-2 Cell Monolayers
Pharmaceutical Research, 1998Co-Authors: Yuanchao Zhang, Leslie Z. BenetAbstract:Purpose. Here we characterized the transport properties of morpholine-urea-phenylalanine- homophenylalanine-vinylsulfone-phenyl (K02), a newly developed peptidomimetic Cysteine Protease Inhibitor, across monolayers of P-gp-expressed MDR1 transfected MDCK cells (MDR1-MDCK) and Caco-2 cells.
Yuanchao Zhang - One of the best experts on this subject based on the ideXlab platform.
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8–10 wk old, n = 3–6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 ± 4.4 to 102 ± 24 mg · min/liter and decreased K02 oral plasma clearance from 3810 ± 1620 to 306 ± 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 ± 17 to 107 ± 14 mg · min/liter) and clearance (from 110 ± 22 to 95 ± 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 ± 1.4 to 31.0 ± 7.5% (P
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T Lin, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8-10 wk old, n = 3-6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 +/- 4.4 to 102 +/- 24 mg . min/liter and decreased K02 oral plasma clearance from 3810 +/- 1620 to 306 +/- 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 +/- 17 to 107 +/- 14 mg . min/liter) and clearance (from 110 +/- 22 to 95 +/- 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 +/- 1.4 to 31.0 +/- 7.5% (P < .001). In summary, ketoconazole, a dual Inhibitor of CYP3A and P-glycoprotein, can effectively increase K02 oral bioavailability by inhibiting the CYP3A/P-gp absorption barrier in the small intestine.
-
overlapping substrate specificities of cytochrome p450 3a and p glycoprotein for a novel Cysteine Protease Inhibitor
Drug Metabolism and Disposition, 1998Co-Authors: Yuanchao Zhang, Leslie Z. BenetAbstract:K02 (morpholine-urea-Phe-Hphe-vinylsulfone), a newly developed peptidomimetic, acts as a potent Cysteine Protease Inhibitor, especially of cathepsins B and L (which are associated with cancer progression) and cruzain (a Cysteine Protease of Trypanosoma cruzi , which is responsible for Chagas’ disease). Here we investigated features of the disposition of K02 using in vitro systems, characterizing the interaction of the drug with human cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), a mediator of multidrug resistance (MDR) to cancer chemotherapy and a countertransporter in the intestine that limits oral drug bioavailability. P-gp functions as an ATP-dependent drug efflux pump to reduce intracellular cytotoxic concentrations. An HPLC assay was developed to analyze K02 and its metabolites formed in human liver microsomes. Three major primary metabolites were determined by LC/MS/MS to be hydroxylated products of the parent compound. A rabbit anti-CYP3A polyclonal antibody (200 μl antibody/mg microsomal protein) produced 75–94% inhibition of the formation of these three hydroxylated metabolites. Ketoconazole (5 μM), a selective CYP3A Inhibitor, produced up to 75% inhibition, whereas other CYP-specific Inhibitors, i.e. quinidine (CYP2D6), 7,8-benzoflavone (CYP1A2), and sulfaphenazole (CYP2C9), showed no significant effects. An identical metabolite formation profile for K02 was observed with cDNA-expressed human CYP3A4 (Gentest). These data demonstrate that K02 is a substrate for CYP3A. Formation of 1′-hydroxymidazolam, the primary human midazolam metabolite, was markedly inhibited by K02 via competitive processes, which suggests the potential for drug-drug interactions of K02 with other CYP3A substrates. K02 significantly inhibited the photoaffinity labeling of P-gp with azidopine and LU-49888, a photoaffinity analogue of verapamil. Transport studies with [ 14 C]K02, using MDR1 -transfected Madin-Darby canine kidney cell monolayers in the Transwell system, demonstrated that the basolateral-to-apical flux of K02 across MDR1 -transfected Madin-Darby canine kidney cells was markedly greater than the apical-to-basolateral flux (ratio of 63 with 10 μM [ 14 C]K02). This suggests that K02 is also a P-gp substrate. These studies are important for formulating strategies to increase the absorption and/or decrease the elimination of K02 and to optimize its delivery to malignant cells and parasite-infected host cells.
-
Characterization of P-glycoprotein Mediated Transport of K02, a Novel Vinylsulfone Peptidomimetic Cysteine Protease Inhibitor, Across MDR1-MDCK and Caco-2 Cell Monolayers
Pharmaceutical Research, 1998Co-Authors: Yuanchao Zhang, Leslie Z. BenetAbstract:Purpose. Here we characterized the transport properties of morpholine-urea-phenylalanine- homophenylalanine-vinylsulfone-phenyl (K02), a newly developed peptidomimetic Cysteine Protease Inhibitor, across monolayers of P-gp-expressed MDR1 transfected MDCK cells (MDR1-MDCK) and Caco-2 cells.
Yuji Moriyasu - One of the best experts on this subject based on the ideXlab platform.
-
detecting autophagy in arabidopsis roots by membrane permeable Cysteine Protease Inhibitor e 64d and endocytosis tracer fm4 64
Plant Signaling & Behavior, 2011Co-Authors: Yuumi Ohye, Yuko Inoue, Yuji MoriyasuAbstract:Autophagy is the process by which cells degrade their own components in lysosomes or vacuoles. Autophagy in tobacco BY-2 cells cultured in sucrose-free medium takes place in formed, autolysosomes in the presence of a Cysteine Protease Inhibitor. The autolysosomes in BY-2 cells are located in the endocytotic pathway and thus can be stained with fluorescent endocytosis marker FM4-64. In the present study, in order to detect autophagy in the root cells of Arabidopsis, we incubated root tips from Arabidopsis seedlings in culture medium containing the membrane-permeable Cysteine Protease Inhibitor E-64d and FM4-64, and examined whether autolysosomes stained with FM4-64 are accumulated. The results suggest that autophagy accompanying the formation of autolysosomes also occurs in Arabidopsis root cells. Such autophagy appeared to occur constitutively in the root cells in nutrient-sufficient culture medium. Even in atg5 mutants in which an autophagy-related gene is disrupted, accumulation of the structures stained with FM4-64, which likely correspond to autolysosomes, was seen although at lower level than in wild type roots.
-
Detecting autophagy in Arabidopsis roots by membrane-permeable Cysteine Protease Inhibitor E-64d and endocytosis tracer FM4–64
Plant Signaling & Behavior, 2011Co-Authors: Yuko Inoue, Yuji MoriyasuAbstract:Autophagy is the process by which cells degrade their own components in lysosomes or vacuoles. Autophagy in tobacco BY-2 cells cultured in sucrose-free medium takes place in formed, autolysosomes in the presence of a Cysteine Protease Inhibitor. The autolysosomes in BY-2 cells are located in the endocytotic pathway and thus can be stained with fluorescent endocytosis marker FM4-64. In the present study, in order to detect autophagy in the root cells of Arabidopsis, we incubated root tips from Arabidopsis seedlings in culture medium containing the membrane-permeable Cysteine Protease Inhibitor E-64d and FM4-64, and examined whether autolysosomes stained with FM4-64 are accumulated. The results suggest that autophagy accompanying the formation of autolysosomes also occurs in Arabidopsis root cells. Such autophagy appeared to occur constitutively in the root cells in nutrient-sufficient culture medium. Even in atg5 mutants in which an autophagy-related gene is disrupted, accumulation of the structures stained with FM4-64, which likely correspond to autolysosomes, was seen although at lower level than in wild type roots.
Takashi Izumi - One of the best experts on this subject based on the ideXlab platform.
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8–10 wk old, n = 3–6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 ± 4.4 to 102 ± 24 mg · min/liter and decreased K02 oral plasma clearance from 3810 ± 1620 to 306 ± 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 ± 17 to 107 ± 14 mg · min/liter) and clearance (from 110 ± 22 to 95 ± 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 ± 1.4 to 31.0 ± 7.5% (P
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T Lin, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8-10 wk old, n = 3-6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 +/- 4.4 to 102 +/- 24 mg . min/liter and decreased K02 oral plasma clearance from 3810 +/- 1620 to 306 +/- 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 +/- 17 to 107 +/- 14 mg . min/liter) and clearance (from 110 +/- 22 to 95 +/- 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 +/- 1.4 to 31.0 +/- 7.5% (P < .001). In summary, ketoconazole, a dual Inhibitor of CYP3A and P-glycoprotein, can effectively increase K02 oral bioavailability by inhibiting the CYP3A/P-gp absorption barrier in the small intestine.
Yunsheng Hsieh - One of the best experts on this subject based on the ideXlab platform.
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8–10 wk old, n = 3–6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 ± 4.4 to 102 ± 24 mg · min/liter and decreased K02 oral plasma clearance from 3810 ± 1620 to 306 ± 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 ± 17 to 107 ± 14 mg · min/liter) and clearance (from 110 ± 22 to 95 ± 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 ± 1.4 to 31.0 ± 7.5% (P
-
effects of ketoconazole on the intestinal metabolism transport and oral bioavailability of k02 a novel vinylsulfone peptidomimetic Cysteine Protease Inhibitor and a p450 3a p glycoprotein dual substrate in male sprague dawley rats
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T Lin, Leslie Z. BenetAbstract:We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic Cysteine Protease Inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8-10 wk old, n = 3-6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 +/- 4.4 to 102 +/- 24 mg . min/liter and decreased K02 oral plasma clearance from 3810 +/- 1620 to 306 +/- 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 +/- 17 to 107 +/- 14 mg . min/liter) and clearance (from 110 +/- 22 to 95 +/- 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 +/- 1.4 to 31.0 +/- 7.5% (P < .001). In summary, ketoconazole, a dual Inhibitor of CYP3A and P-glycoprotein, can effectively increase K02 oral bioavailability by inhibiting the CYP3A/P-gp absorption barrier in the small intestine.
