The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Wei Ning Chen - One of the best experts on this subject based on the ideXlab platform.
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Metabolic profiling of HepG2 cells incubated with S(−) and R(+) enantiomers of anti-coagulating drug warfarin
Metabolomics, 2011Co-Authors: Jing Bai, Chi Bun Ching, Balram Chowbay, Ming Xuan Wang, Wei Ning ChenAbstract:Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(−) and R(+) and undergoes stereoselective metabolism, with the S(−) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(−) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(−) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(−) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(−) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy.
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Metabolic profiling of HepG2 cells incubated with S(-) and R(+) enantiomers of anti-coagulating drug warfarin.
Metabolomics : Official journal of the Metabolomic Society, 2010Co-Authors: Jing Bai, Chi Bun Ching, Balram Chowbay, Ming Xuan Wang, Wei Ning ChenAbstract:Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(−) and R(+) and undergoes stereoselective metabolism, with the S(−) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(−) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(−) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(−) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(−) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy.
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A comparative proteomic analysis of HepG2 cells incubated by S(−) and R(+) enantiomers of anti‐coagulating drug warfarin
Proteomics, 2010Co-Authors: Jing Bai, Laleh Sadrolodabaee, Chi Bun Ching, Balram Chowbay, Wei Ning ChenAbstract:Warfarin is a commonly prescribed oral anti-coagulant with narrow therapeutic index. It interferes with vitamin K cycle to achieve anti-coagulating effects. Warfarin has two enantiomers, S(-) and R(+) and undergoes stereoselective metabolism, with the S(-) enantiomer being more effective. We reported that the intracellular protein profile in HepG2 cells incubated with S(-) and R(+) warfarin, using iTRAQ-coupled 2-D LC-MS/MS. In samples incubated with S(-) and R(+) warfarin alone, the multi-task protein Protein SET showed significant elevation in cells incubated with S(-) warfarin but not in those incubated with R(+) warfarin. In cells incubated with individual enantiomers of warfarin in the presence of vitamin K, protein disulfide isomerase A3 which is known as a glucose-regulated protein, in cells incubated with S(-) warfarin was found to be down-regulated compared to those incubated with R(+) warfarin. In addition, Protein DJ-1 and 14-3-3 Proteinsigma were down-regulated in cells incubated with either S(-) or R(+) warfarin regardless of the presence of vitamin K. Our results indicated that Protein DJ-1 may act as an enzyme for expression of essential enzymes in vitamin K cycle. Taken together, our findings provided molecular evidence on a comprehensive protein profile on warfarin-cell interaction, which may shed new lights on future improvement of warfarin therapy.
Naohito Fujishima - One of the best experts on this subject based on the ideXlab platform.
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Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
Clinica Chimica Acta, 2011Co-Authors: Masatomo Miura, Naoto Takahashi, Syu-ichi Kanno, Shoutaro Kato, Miho Nara, Mitsugu Itoh, Hirobumi Saitoh, Tomoko Yoshioka, Yoshihiro Kameoka, Naohito FujishimaAbstract:Abstract Background Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate ( S )-warfarin, and not the CYP3A4 substrate ( R )-warfarin, increased with itraconazole coadministration. Case A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200 mg/day) and was started on a warfarin dose of 2.0 mg/day. The plasma concentrations of ( S )- and ( R )-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of ( S )- and ( R )-warfarin were 341 and 605 ng/mL, respectively (INR 1.38). The concentration of ( R )-warfarin was not affected by itraconazole; however, the final ( S )-warfarin concentration had increased 7.3-fold. The ( S )-warfarin/( S )-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Conclusions Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.
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Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
Clinica Chimica Acta, 2011Co-Authors: Masatomo Miura, Naoto Takahashi, Syu-ichi Kanno, Shoutaro Kato, Miho Nara, Mitsugu Itoh, Hirobumi Saitoh, Tomoko Yoshioka, Yoshihiro Kameoka, Naohito FujishimaAbstract:Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-warfarin, and not the CYP3A4 substrate (R)-warfarin, increased with itraconazole coadministration. A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200mg/day) and was started on a warfarin dose of 2.0mg/day. The plasma concentrations of (S)- and (R)-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-warfarin were 341 and 605ng/mL, respectively (INR 1.38). The concentration of (R)-warfarin was not affected by itraconazole; however, the final (S)-warfarin concentration had increased 7.3-fold. The (S)-warfarin/(S)-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole. Copyright © 2011 Elsevier B.V. All rights reserved.
Jing Bai - One of the best experts on this subject based on the ideXlab platform.
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Metabolic profiling of HepG2 cells incubated with S(−) and R(+) enantiomers of anti-coagulating drug warfarin
Metabolomics, 2011Co-Authors: Jing Bai, Chi Bun Ching, Balram Chowbay, Ming Xuan Wang, Wei Ning ChenAbstract:Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(−) and R(+) and undergoes stereoselective metabolism, with the S(−) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(−) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(−) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(−) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(−) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy.
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Metabolic profiling of HepG2 cells incubated with S(-) and R(+) enantiomers of anti-coagulating drug warfarin.
Metabolomics : Official journal of the Metabolomic Society, 2010Co-Authors: Jing Bai, Chi Bun Ching, Balram Chowbay, Ming Xuan Wang, Wei Ning ChenAbstract:Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(−) and R(+) and undergoes stereoselective metabolism, with the S(−) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(−) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(−) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(−) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(−) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy.
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A comparative proteomic analysis of HepG2 cells incubated by S(−) and R(+) enantiomers of anti‐coagulating drug warfarin
Proteomics, 2010Co-Authors: Jing Bai, Laleh Sadrolodabaee, Chi Bun Ching, Balram Chowbay, Wei Ning ChenAbstract:Warfarin is a commonly prescribed oral anti-coagulant with narrow therapeutic index. It interferes with vitamin K cycle to achieve anti-coagulating effects. Warfarin has two enantiomers, S(-) and R(+) and undergoes stereoselective metabolism, with the S(-) enantiomer being more effective. We reported that the intracellular protein profile in HepG2 cells incubated with S(-) and R(+) warfarin, using iTRAQ-coupled 2-D LC-MS/MS. In samples incubated with S(-) and R(+) warfarin alone, the multi-task protein Protein SET showed significant elevation in cells incubated with S(-) warfarin but not in those incubated with R(+) warfarin. In cells incubated with individual enantiomers of warfarin in the presence of vitamin K, protein disulfide isomerase A3 which is known as a glucose-regulated protein, in cells incubated with S(-) warfarin was found to be down-regulated compared to those incubated with R(+) warfarin. In addition, Protein DJ-1 and 14-3-3 Proteinsigma were down-regulated in cells incubated with either S(-) or R(+) warfarin regardless of the presence of vitamin K. Our results indicated that Protein DJ-1 may act as an enzyme for expression of essential enzymes in vitamin K cycle. Taken together, our findings provided molecular evidence on a comprehensive protein profile on warfarin-cell interaction, which may shed new lights on future improvement of warfarin therapy.
Masatomo Miura - One of the best experts on this subject based on the ideXlab platform.
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Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
Clinica Chimica Acta, 2011Co-Authors: Masatomo Miura, Naoto Takahashi, Syu-ichi Kanno, Shoutaro Kato, Miho Nara, Mitsugu Itoh, Hirobumi Saitoh, Tomoko Yoshioka, Yoshihiro Kameoka, Naohito FujishimaAbstract:Abstract Background Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate ( S )-warfarin, and not the CYP3A4 substrate ( R )-warfarin, increased with itraconazole coadministration. Case A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200 mg/day) and was started on a warfarin dose of 2.0 mg/day. The plasma concentrations of ( S )- and ( R )-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of ( S )- and ( R )-warfarin were 341 and 605 ng/mL, respectively (INR 1.38). The concentration of ( R )-warfarin was not affected by itraconazole; however, the final ( S )-warfarin concentration had increased 7.3-fold. The ( S )-warfarin/( S )-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Conclusions Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.
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Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
Clinica Chimica Acta, 2011Co-Authors: Masatomo Miura, Naoto Takahashi, Syu-ichi Kanno, Shoutaro Kato, Miho Nara, Mitsugu Itoh, Hirobumi Saitoh, Tomoko Yoshioka, Yoshihiro Kameoka, Naohito FujishimaAbstract:Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-warfarin, and not the CYP3A4 substrate (R)-warfarin, increased with itraconazole coadministration. A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200mg/day) and was started on a warfarin dose of 2.0mg/day. The plasma concentrations of (S)- and (R)-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-warfarin were 341 and 605ng/mL, respectively (INR 1.38). The concentration of (R)-warfarin was not affected by itraconazole; however, the final (S)-warfarin concentration had increased 7.3-fold. The (S)-warfarin/(S)-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole. Copyright © 2011 Elsevier B.V. All rights reserved.
Hiroshi Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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monkey liver cytochrome p450 2c19 is involved in r and s warfarin 7 hydroxylation
Biochemical Pharmacology, 2012Co-Authors: Yoshio Hosoi, Masahiro Utoh, Makiko Shimizu, Yasuhiro Uno, Norie Murayama, Hideki Fujino, Mitsunori Shukuya, Kazuhide Iwasaki, Hiroshi YamazakiAbstract:Abstract Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R - and S -warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R - and S -warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R - and S -warfarin 7-hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S -warfarin 7-hydroxylation. R -Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by α-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S -warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R - and S -warfarin 7-hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R - and S -warfarin 6-hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V max and low K m values for R -warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S -warfarin 7-hydroxylation with V max and V max / K m values comparable to those for recombinant human P450 2C9. R -warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R - and S -warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S -warfarin 7-hydroxylation.
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Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers.
Biochemical pharmacology, 1997Co-Authors: Hiroshi Yamazaki, Tsutomu ShimadaAbstract:Human liver microsomes had about 8-fold higher 7-hydroxylation activities for S-warfarin than for R-Warfarin. Activities of racemic warfarin 7-hydroxylation by liver microsomes of 35 human samples correlated more closely with those of S-warfarin 7-hydroxylation (r = 0.95) than with those of R-Warfarin 7-hydroxylation (r = 0.69). The correlation coefficient between R-Warfarin 7-hydroxylation and 7-ethoxyresorufin O-deethylation activities was 0.73 in these human samples, suggesting that R- and S-warfarin enantiomers are catalyzed by different forms of human cytochrome P450 (P450 or CYP) enzymes. Anti-CYP2C9 antibodies inhibited completely the 7-hydroxylation of S-warfarin, but not R-Warfarin, catalyzed by human liver microsomes, while anti-CYP1A2 inhibited R-Warfarin 7-hydroxylation by about 70%. Interestingly, the racemic warfarin 7-hydroxylation activities (turnover numbers of 1.6 +/- 1.0 pmol/min/mg protein in 35 human samples) were found to be low compared with the S-warfarin 7-hydroxylation activities (4.1 +/- 2.5 pmol/min/mg protein), indicating that R-Warfarin may have affected the CYP2C9-dependent S-warfarin 7-hydroxylation activities when racemic warfarin was used as a substrate. Several P450 inhibitors, as well as R-Warfarin, were examined for their abilities to inhibit S-warfarin 7-hydroxylation; we found that R-Warfarin was a non-competitive inhibitor with a Ki value of about 150 microM, whereas both tolbutamide and sulfaphenazole were competitive inhibitors with Ki values of about 100 and 0.5 microM, respectively, for S-warfarin 7-hydroxylation activities. These results suggest that R- and S-warfarin enantiomers are catalyzed principally by CYP1A2 and CYP2C9, respectively, in human liver microsomes, and that the pharmacokinetic properties of S-warfarin may be altered by R-Warfarin in vivo when racemic warfarin is administered clinically to humans.
