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Jt T Backman - One of the best experts on this subject based on the ideXlab platform.
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Gemfibrozil impairs imatinib absorption and inhibits the cyp2c8 mediated formation of its main metabolite
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Anne M Filppula, Mikko Niemi, Pertti J. Neuvonen, Aleksi Tornio, Jt T BackmanAbstract:Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered Gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, Gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration–time curve (AUC0–∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0–∞ of imatinib was unaffected. Furthermore, Gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with Gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption. Clinical Pharmacology & Therapeutics (2013); 94 3, 383–393. doi:10.1038/clpt.2013.92
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Gemfibrozil Is a Strong Inactivator of CYP2C8 in Very Small Multiple Doses
Clinical pharmacology and therapeutics, 2012Co-Authors: Johanna Honkalammi, Mikko Niemi, Pertti J. Neuvonen, Jt T BackmanAbstract:Therapeutic doses of Gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of Gemfibrozil 1-O-β-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of Gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration–time curve from 0 to infinity (AUC0–∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of Gemfibrozil, respectively, as compared with the control phase (P 70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, Gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small Gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.
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Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses
Drug metabolism and disposition: the biological fate of chemicals, 2011Co-Authors: Johanna Honkalammi, Mikko Niemi, Pertti J. Neuvonen, Jt T BackmanAbstract:Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of Gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of Gemfibrozil or placebo. Concentrations of plasma repaglinide, Gemfibrozil, their metabolites, and blood glucose were measured. A single Gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P 95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of Gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.
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Gemfibrozil markedly increases the plasma concentrations of montelukast a previously unrecognized role for cyp2c8 in the metabolism of montelukast
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Tiina Karonen, Mikko Niemi, Pertti J. Neuvonen, Jouko Laitila, Anne M Filppula, Jt T BackmanAbstract:According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered Gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half-life (t(1/2)) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P 90% (P < 0.001). In human liver microsomes, Gemfibrozil 1-O-beta glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35-fold more potently than did Gemfibrozil (half-maximal inhibitory concentration (IC(50)) 3.0 and 107 micromol/l, respectively). In conclusion, Gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.
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cyp2c8 activity recovers within 96 hours after Gemfibrozil dosing estimation of cyp2c8 half life using repaglinide as an in vivo probe
Drug Metabolism and Disposition, 2009Co-Authors: Jt T Backman, Mikko Niemi, Aleksi Tornio, Mikko Neuvonen, Johanna Honkalammi, Kaisa J Kurkinen, Pertti J. NeuvonenAbstract:Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of Gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of Gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last Gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after Gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after Gemfibrozil and Gemfibrozil 1-O-beta-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after Gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after Gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.
Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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Gemfibrozil impairs imatinib absorption and inhibits the cyp2c8 mediated formation of its main metabolite
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Anne M Filppula, Mikko Niemi, Pertti J. Neuvonen, Aleksi Tornio, Jt T BackmanAbstract:Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered Gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, Gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration–time curve (AUC0–∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0–∞ of imatinib was unaffected. Furthermore, Gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with Gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption. Clinical Pharmacology & Therapeutics (2013); 94 3, 383–393. doi:10.1038/clpt.2013.92
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Gemfibrozil Is a Strong Inactivator of CYP2C8 in Very Small Multiple Doses
Clinical pharmacology and therapeutics, 2012Co-Authors: Johanna Honkalammi, Mikko Niemi, Pertti J. Neuvonen, Jt T BackmanAbstract:Therapeutic doses of Gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of Gemfibrozil 1-O-β-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of Gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration–time curve from 0 to infinity (AUC0–∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of Gemfibrozil, respectively, as compared with the control phase (P 70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, Gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small Gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.
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Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses
Drug metabolism and disposition: the biological fate of chemicals, 2011Co-Authors: Johanna Honkalammi, Mikko Niemi, Pertti J. Neuvonen, Jt T BackmanAbstract:Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of Gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of Gemfibrozil or placebo. Concentrations of plasma repaglinide, Gemfibrozil, their metabolites, and blood glucose were measured. A single Gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P 95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of Gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.
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Gemfibrozil markedly increases the plasma concentrations of montelukast a previously unrecognized role for cyp2c8 in the metabolism of montelukast
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Tiina Karonen, Mikko Niemi, Pertti J. Neuvonen, Jouko Laitila, Anne M Filppula, Jt T BackmanAbstract:According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered Gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half-life (t(1/2)) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P 90% (P < 0.001). In human liver microsomes, Gemfibrozil 1-O-beta glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35-fold more potently than did Gemfibrozil (half-maximal inhibitory concentration (IC(50)) 3.0 and 107 micromol/l, respectively). In conclusion, Gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.
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cyp2c8 activity recovers within 96 hours after Gemfibrozil dosing estimation of cyp2c8 half life using repaglinide as an in vivo probe
Drug Metabolism and Disposition, 2009Co-Authors: Jt T Backman, Mikko Niemi, Aleksi Tornio, Mikko Neuvonen, Johanna Honkalammi, Kaisa J Kurkinen, Pertti J. NeuvonenAbstract:Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of Gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of Gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last Gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after Gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after Gemfibrozil and Gemfibrozil 1-O-beta-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after Gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after Gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.
Leila Khalaj - One of the best experts on this subject based on the ideXlab platform.
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Gemfibrozil Pretreatment Resulted in a Sexually Dimorphic Outcome in the Rat Models of Global Cerebral Ischemia–Reperfusion via Modulation of Mitochondrial Pro-survival and Apoptotic Cell Death Factors as well as MAPKs
Journal of Molecular Neuroscience, 2013Co-Authors: Fatemeh Mohagheghi, Abolhassan Ahmadiani, Behrouz Rahmani, Fatemeh Moradi, Nathalie Romond, Leila KhalajAbstract:Inducers of mitochondrial biogenesis are widely under investigation for use in a novel therapeutic approach in neurodegenerative disorders. The ability of Gemfibrozil, a fibrate, is investigated for the first time to modulate mitochondrial pro-survival factors involved in the mitochondrial biogenesis signaling pathway, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factor (NRF-1), and mitochondrial transcription factor A (TFAM) in the brain. Gemfibozil is clinically administered to control hyperlipidemia. It secondarily prevents cardiovascular events such as cardiac arrest in susceptible patients. In this study, pretreatment of animals with Gemfibrozil prior to ischemia–reperfusion (I/R) resulted in a sexually dimorphic outcome. While the expression of NRF-1 and TFAM were induced in Gemfibrozil-pretreated met-estrous females, they were suppressed in males. Gemfibrozil also proved to be neuroprotective in met-estrous females, as it inhibited caspase-dependent apoptosis while in males it led to hippocampal neurodegeneration via activation of both the caspase-dependent and caspase-independent apoptosis. In the mitogen-activated protein kinase (MAPKs) pathway, Gemfibrozil pretreatment induced the expression of extracellular signal-regulated kinases (ERK1/2) in met-estrous females and reduced it in males. These findings correlatively point to the sexual-dimorphic effects of Gemfibrozil in global cerebral I/R context by affecting important factors involved in the mitochondrial biogenesis, MAPKs, and apoptotic cell death pathways.
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Gemfibrozil Pretreatment Resulted in a Sexually Dimorphic Outcome in the Rat Models of Global Cerebral Ischemia–Reperfusion via Modulation of Mitochondrial Pro-survival and Apoptotic Cell Death Factors as well as MAPKs
Journal of Molecular Neuroscience, 2013Co-Authors: Fatemeh Mohagheghi, Abolhassan Ahmadiani, Behrouz Rahmani, Fatemeh Moradi, Nathalie Romond, Leila KhalajAbstract:Inducers of mitochondrial biogenesis are widely under investigation for use in a novel therapeutic approach in neurodegenerative disorders. The ability of Gemfibrozil, a fibrate, is investigated for the first time to modulate mitochondrial pro-survival factors involved in the mitochondrial biogenesis signaling pathway, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factor (NRF-1), and mitochondrial transcription factor A (TFAM) in the brain. Gemfibozil is clinically administered to control hyperlipidemia. It secondarily prevents cardiovascular events such as cardiac arrest in susceptible patients. In this study, pretreatment of animals with Gemfibrozil prior to ischemia–reperfusion (I/R) resulted in a sexually dimorphic outcome. While the expression of NRF-1 and TFAM were induced in Gemfibrozil-pretreated met-estrous females, they were suppressed in males. Gemfibrozil also proved to be neuroprotective in met-estrous females, as it inhibited caspase-dependent apoptosis while in males it led to hippocampal neurodegeneration via activation of both the caspase-dependent and caspase-independent apoptosis. In the mitogen-activated protein kinase (MAPKs) pathway, Gemfibrozil pretreatment induced the expression of extracellular signal-regulated kinases (ERK1/2) in met-estrous females and reduced it in males. These findings correlatively point to the sexual-dimorphic effects of Gemfibrozil in global cerebral I/R context by affecting important factors involved in the mitochondrial biogenesis, MAPKs, and apoptotic cell death pathways.
Hidetaka Kamimura - One of the best experts on this subject based on the ideXlab platform.
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The UDP-glucuronosyltransferase 2B7 isozyme is responsible for Gemfibrozil glucuronidation in the human liver.
Drug Metabolism and Disposition, 2007Co-Authors: Yuji Mano, Takashi Usui, Hidetaka KamimuraAbstract:Gemfibrozil, a fibrate hypolipidemic agent, is eliminated in humans by glucuronidation. A Gemfibrozil glucuronide has been reported to show time-dependent inhibition of cytochrome P450 2C8. Comprehensive assessment of the drug interaction between Gemfibrozil and cytochrome P450 2C8 substrates requires a clear understanding of Gemfibrozil glucuronidation. However, the primary UDP-glucuronosyltransferase (UGT) isozymes responsible for Gemfibrozil glucuronidation remain to be determined. Here, we identified the main UGT isozymes involved in Gemfibrozil glucuronidation. Evaluation of 12 recombinant human UGT isozymes shows Gemfibrozil glucuronidation activity in UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, with UGT2B7 showing the highest activity. The kinetics of Gemfibrozil glucuronidation in pooled human liver microsomes (HLMs) follows Michaelis-Menten kinetics with high and low affinity components. The high affinity K m value was 2.5 μM, which is similar to the K m value of Gemfibrozil glucuronidation in recombinant UGT2B7 (2.2 μM). In 16 HLMs, a significant correlation was observed between Gemfibrozil glucuronidation and both morphine 3-OH glucuronidation ( r = 0.966, p < 0.0001) and flurbiprofen glucuronidation ( r = 0.937, p < 0.0001), two reactions mainly catalyzed by UGT2B7, whereas no significant correlation was observed between Gemfibrozil glucuronidation and either estradiol 3β-glucuronidation and propofol glucuronidation, two reactions catalyzed by UGT1A1 and UGT1A9, respectively. Flurbiprofen and mefenamic acid inhibited Gemfibrozil glucuronidation in HLMs with similar IC50 values to those reported in recombinant UGT2B7. These results suggest that UGT2B7 is the main isozyme responsible for Gemfibrozil glucuronidation in humans.
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The UDP-glucuronosyltransferase 2B7 isozyme is responsible for Gemfibrozil glucuronidation in the human liver.
Drug metabolism and disposition: the biological fate of chemicals, 2007Co-Authors: Yuji Mano, Takashi Usui, Hidetaka KamimuraAbstract:Gemfibrozil, a fibrate hypolipidemic agent, is eliminated in humans by glucuronidation. A Gemfibrozil glucuronide has been reported to show time-dependent inhibition of cytochrome P450 2C8. Comprehensive assessment of the drug interaction between Gemfibrozil and cytochrome P450 2C8 substrates requires a clear understanding of Gemfibrozil glucuronidation. However, the primary UDP-glucuronosyltransferase (UGT) isozymes responsible for Gemfibrozil glucuronidation remain to be determined. Here, we identified the main UGT isozymes involved in Gemfibrozil glucuronidation. Evaluation of 12 recombinant human UGT isozymes shows Gemfibrozil glucuronidation activity in UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, with UGT2B7 showing the highest activity. The kinetics of Gemfibrozil glucuronidation in pooled human liver microsomes (HLMs) follows Michaelis-Menten kinetics with high and low affinity components. The high affinity K(m) value was 2.5 microM, which is similar to the K(m) value of Gemfibrozil glucuronidation in recombinant UGT2B7 (2.2 microM). In 16 HLMs, a significant correlation was observed between Gemfibrozil glucuronidation and both morphine 3-OH glucuronidation (r = 0.966, p < 0.0001) and flurbiprofen glucuronidation (r = 0.937, p < 0.0001), two reactions mainly catalyzed by UGT2B7, whereas no significant correlation was observed between Gemfibrozil glucuronidation and either estradiol 3beta-glucuronidation and propofol glucuronidation, two reactions catalyzed by UGT1A1 and UGT1A9, respectively. Flurbiprofen and mefenamic acid inhibited Gemfibrozil glucuronidation in HLMs with similar IC(50) values to those reported in recombinant UGT2B7. These results suggest that UGT2B7 is the main isozyme responsible for Gemfibrozil glucuronidation in humans.
Sidney Tam - One of the best experts on this subject based on the ideXlab platform.
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Hyperlipidemia after renal transplantation : treatment with Gemfibrozil
Nephron, 1994Co-Authors: Tak Mao Chan, Ignatius K.p. Cheng, Sidney TamAbstract:Thirty-eight renal allograft recipients who had persistent hyperlipidemia and stable renal function 27.8 ± 18.2 months after renal transplantation were treated with Gemfibrozil. Gemfibrozil therapy re