The Experts below are selected from a list of 1926 Experts worldwide ranked by ideXlab platform
Stephan Krahenbuhl - One of the best experts on this subject based on the ideXlab platform.
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metamizole is a moderate Cytochrome P450 Inducer via the constitutive androstane receptor and a weak inhibitor of cyp1a2
Clinical Pharmacology & Therapeutics, 2021Co-Authors: Fabio Bachmann, Urs Duthaler, Henriette Meyer Zu E Schwabedissen, Maxim Puchkov, Jorg Huwyler, Manuel Haschke, Stephan KrahenbuhlAbstract:Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces Cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP Inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance.
Fabio Bachmann - One of the best experts on this subject based on the ideXlab platform.
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metamizole is a moderate Cytochrome P450 Inducer via the constitutive androstane receptor and a weak inhibitor of cyp1a2
Clinical Pharmacology & Therapeutics, 2021Co-Authors: Fabio Bachmann, Urs Duthaler, Henriette Meyer Zu E Schwabedissen, Maxim Puchkov, Jorg Huwyler, Manuel Haschke, Stephan KrahenbuhlAbstract:Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces Cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP Inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance.
Brian J Houston - One of the best experts on this subject based on the ideXlab platform.
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Houston: Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes and the intact liver, submitted for publication
2016Co-Authors: David J Carlile, K Zomorodi, Brian J HoustonAbstract:Microsomal protein recovery and hepatocellularity have been de-termined and investigated as scaling factors for interrelating clear-ance by hepatic microsomes, freshly isolated hepatocytes and whole liver from untreated (UT) rats and rats treated with either the Cytochrome P450 Inducer phenobarbital (PB) or dexamethasone (DEX). Hepatocellularity in UT rats (1.1 3 108 hepatocytes/g liver) was not significantly different after either PB or DEX induction (1.1 and 1.3 3 108 hepatocytes/g liver, respectively). However the mi-crosomal protein recovery index, which provides a scaling factor that is inversely related to the efficiency of the microsomal prep-aration procedure, was 47 mg/g liver in both PB and DEX micro-somes and differs from UT rats (60 mg/g liver). These contrasting findings are consistent with the interlaboratory trends in the liter-ature, indicating that, although hepatocellularity estimates are in good accord, microsomal recovery can vary 2-fold; this has impli
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scaling factors to relate drug metabolic clearance in hepatic microsomes isolated hepatocytes and the intact liver studies with induced livers involving diazepam
Drug Metabolism and Disposition, 1997Co-Authors: David J Carlile, K Zomorodi, Brian J HoustonAbstract:Microsomal protein recovery and hepatocellularity have been determined and investigated as scaling factors for interrelating clearance by hepatic microsomes, freshly isolated hepatocytes and whole liver from untreated (UT) rats and rats treated with either the Cytochrome P450 Inducer phenobarbital (PB) or dexamethasone (DEX). Hepatocellularity in UT rats (1.1 3 10 8 hepatocytes/g liver) was not significantly different after either PB or DEX induction (1.1 and 1.3 3 10 8 hepatocytes/g liver, respectively). However the microsomal protein recovery index, which provides a scaling factor that is inversely related to the efficiency of the microsomal preparation procedure, was 47 mg/g liver in both PB and DEX microsomes and differs from UT rats (60 mg/g liver). These contrasting findings are consistent with the interlaboratory trends in the literature, indicating that, although hepatocellularity estimates are in good accord, microsomal recovery can vary 2-fold; this has implications for scaling. The oxidation of diazepam to its three primary metabolites was measured in PB and DEX microsomes and hepatocytes and the scaling factors were applied to these data and previously reported UT data. Marked changes in kinetics occur on induction resulting in a shift in the major pathway. In particular, 3-hydroxylation is induced over 20-fold by DEX. Diazepam CLint was determined in vivo after administration of a bolus dose into the hepatic portal vein of UT, PB, and DEX rats; values of 127, 191, and 323 ml/min/SRW (where SRW is a standard rat weight of 250 g), respectively, were obtained. Using these scaling factors, the hepatocyte predictions of CLint were excellent (99, 144, and 297 ml/min/SRW for UT, PB, and DEX, respectively), whereas only the DEX prediction (248 ml/ min/SRW) was accurate for the microsomal system, with a substantial underprediction for UT and PB (46 and 68 ml/min/SRW, respectively). Evidence is presented for product inhibition, resulting from accumulation of primary metabolites within the microsomal preparation, as the mechanism responsible for this underprediction. These results illustrate that the scaling factor approach is applicable to induced livers in which both Cytochrome P450 complement and zonal distribution are altered. These data, together with our previous studies, demonstrate that CLint in cells (2.4‐297 ml/ min/SRW), microsomes (2.7‐248 ml/min/SRW), and in vivo (1.5‐323 ml/min/SRW) are related in a linear fashion and hence inherently both in vitro systems are of equal value in predicting in vivo CLint. The use of scaling factors in drug metabolism provides an approach to compare directly kinetic data from two or more in vitro systems and to predict in vivo behavior from in vitro systems. These factors should not be purely empirical in nature, rather they should originate from the anatomical and/or biochemical characteristics of the in vitro system. For example, hepatic microsomal rates of metabolism are usually expressed per milligram of microsomal protein and may be scaled by recognizing the inefficiency of the microsomal isolation procedure by using a microsomal recovery factor. This recovery factor enables the conversion of rates to units of liver weight and hence to the intact animal. Similarly, hepatocyte suspension data, expressed per million cells, require a hepatocellularity number to render such data comparable with other in vitro systems or predictive of the in vivo situation. In assessing the utility of scaling factors using a data base of 25 drugs (1), we found excellent in vivo prediction of metabolic clearance from both microsomes and hepatocytes for low clearance drugs. However, whereas the prediction for high clearance drugs from hepatocytes proved to be equally valuable, underestimation of in vivo high clearance from microsomal data was frequently observed. Further comparison of the relationship between microsomal and hepatocellular clearance suggested that a maximum limit for microsomal clearance may exist. However, because the data used in this later analysis originated from a variety of laboratories, no definitive conclusions could be drawn. In contrast, the main analysis clearly demonstrated the value of microsomal protein recovery index and hepatocellularity as microsomal and hepatocyte scaling factors, respectively. To examine further the scaling factor approach, we have now investigated the scaling of data from hepatic microsomes and hepatocytes from PB 2 - and DEX-treated Sprague-Dawley rats, together
Urs Duthaler - One of the best experts on this subject based on the ideXlab platform.
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metamizole is a moderate Cytochrome P450 Inducer via the constitutive androstane receptor and a weak inhibitor of cyp1a2
Clinical Pharmacology & Therapeutics, 2021Co-Authors: Fabio Bachmann, Urs Duthaler, Henriette Meyer Zu E Schwabedissen, Maxim Puchkov, Jorg Huwyler, Manuel Haschke, Stephan KrahenbuhlAbstract:Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces Cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP Inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance.
David J Carlile - One of the best experts on this subject based on the ideXlab platform.
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Houston: Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes and the intact liver, submitted for publication
2016Co-Authors: David J Carlile, K Zomorodi, Brian J HoustonAbstract:Microsomal protein recovery and hepatocellularity have been de-termined and investigated as scaling factors for interrelating clear-ance by hepatic microsomes, freshly isolated hepatocytes and whole liver from untreated (UT) rats and rats treated with either the Cytochrome P450 Inducer phenobarbital (PB) or dexamethasone (DEX). Hepatocellularity in UT rats (1.1 3 108 hepatocytes/g liver) was not significantly different after either PB or DEX induction (1.1 and 1.3 3 108 hepatocytes/g liver, respectively). However the mi-crosomal protein recovery index, which provides a scaling factor that is inversely related to the efficiency of the microsomal prep-aration procedure, was 47 mg/g liver in both PB and DEX micro-somes and differs from UT rats (60 mg/g liver). These contrasting findings are consistent with the interlaboratory trends in the liter-ature, indicating that, although hepatocellularity estimates are in good accord, microsomal recovery can vary 2-fold; this has impli
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scaling factors to relate drug metabolic clearance in hepatic microsomes isolated hepatocytes and the intact liver studies with induced livers involving diazepam
Drug Metabolism and Disposition, 1997Co-Authors: David J Carlile, K Zomorodi, Brian J HoustonAbstract:Microsomal protein recovery and hepatocellularity have been determined and investigated as scaling factors for interrelating clearance by hepatic microsomes, freshly isolated hepatocytes and whole liver from untreated (UT) rats and rats treated with either the Cytochrome P450 Inducer phenobarbital (PB) or dexamethasone (DEX). Hepatocellularity in UT rats (1.1 3 10 8 hepatocytes/g liver) was not significantly different after either PB or DEX induction (1.1 and 1.3 3 10 8 hepatocytes/g liver, respectively). However the microsomal protein recovery index, which provides a scaling factor that is inversely related to the efficiency of the microsomal preparation procedure, was 47 mg/g liver in both PB and DEX microsomes and differs from UT rats (60 mg/g liver). These contrasting findings are consistent with the interlaboratory trends in the literature, indicating that, although hepatocellularity estimates are in good accord, microsomal recovery can vary 2-fold; this has implications for scaling. The oxidation of diazepam to its three primary metabolites was measured in PB and DEX microsomes and hepatocytes and the scaling factors were applied to these data and previously reported UT data. Marked changes in kinetics occur on induction resulting in a shift in the major pathway. In particular, 3-hydroxylation is induced over 20-fold by DEX. Diazepam CLint was determined in vivo after administration of a bolus dose into the hepatic portal vein of UT, PB, and DEX rats; values of 127, 191, and 323 ml/min/SRW (where SRW is a standard rat weight of 250 g), respectively, were obtained. Using these scaling factors, the hepatocyte predictions of CLint were excellent (99, 144, and 297 ml/min/SRW for UT, PB, and DEX, respectively), whereas only the DEX prediction (248 ml/ min/SRW) was accurate for the microsomal system, with a substantial underprediction for UT and PB (46 and 68 ml/min/SRW, respectively). Evidence is presented for product inhibition, resulting from accumulation of primary metabolites within the microsomal preparation, as the mechanism responsible for this underprediction. These results illustrate that the scaling factor approach is applicable to induced livers in which both Cytochrome P450 complement and zonal distribution are altered. These data, together with our previous studies, demonstrate that CLint in cells (2.4‐297 ml/ min/SRW), microsomes (2.7‐248 ml/min/SRW), and in vivo (1.5‐323 ml/min/SRW) are related in a linear fashion and hence inherently both in vitro systems are of equal value in predicting in vivo CLint. The use of scaling factors in drug metabolism provides an approach to compare directly kinetic data from two or more in vitro systems and to predict in vivo behavior from in vitro systems. These factors should not be purely empirical in nature, rather they should originate from the anatomical and/or biochemical characteristics of the in vitro system. For example, hepatic microsomal rates of metabolism are usually expressed per milligram of microsomal protein and may be scaled by recognizing the inefficiency of the microsomal isolation procedure by using a microsomal recovery factor. This recovery factor enables the conversion of rates to units of liver weight and hence to the intact animal. Similarly, hepatocyte suspension data, expressed per million cells, require a hepatocellularity number to render such data comparable with other in vitro systems or predictive of the in vivo situation. In assessing the utility of scaling factors using a data base of 25 drugs (1), we found excellent in vivo prediction of metabolic clearance from both microsomes and hepatocytes for low clearance drugs. However, whereas the prediction for high clearance drugs from hepatocytes proved to be equally valuable, underestimation of in vivo high clearance from microsomal data was frequently observed. Further comparison of the relationship between microsomal and hepatocellular clearance suggested that a maximum limit for microsomal clearance may exist. However, because the data used in this later analysis originated from a variety of laboratories, no definitive conclusions could be drawn. In contrast, the main analysis clearly demonstrated the value of microsomal protein recovery index and hepatocellularity as microsomal and hepatocyte scaling factors, respectively. To examine further the scaling factor approach, we have now investigated the scaling of data from hepatic microsomes and hepatocytes from PB 2 - and DEX-treated Sprague-Dawley rats, together
