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CYP2B6, CYP3A4, AND CYP2C19 ARE RESPONSIBLE FOR THE IN VITRO N-DEMETHYLATION OF MEPERIDINE IN HUMAN LIVER MICROSOMES

CYP2B6, CYP3A4, AND CYP2C19 ARE RESPONSIBLE FOR THE IN VITRO N-DEMETHYLATION OF MEPERIDINE IN... Abstract Meperidine is an opioid analgesic metabolized in the liver by N -demethylation to normeperidine, a potent stimulant of the central nervous system. The purpose of this study was to identify the human cytochrome P450 (P450) enzymes involved in normeperidine formation. Our in vitro studies included 1) screening 16 expressed P450s for normeperidine formation, 2) kinetic experiments on human liver microsomes and candidate P450s, and 3) correlation and inhibition experiments using human hepatic microsomes. After normalization by its relative abundance in human liver microsomes, CYP2B6, CYP3A4, and CYP2C19 accounted for 57, 28, and 15% of the total intrinsic clearance of meperidine. CYP3A5 and CYP2D6 contributed to < 1%. Formation of normeperidine significantly correlated with CYP2B6-selective S -mephenytoin N -demethylation ( r = 0.88, p < 0.0001 at 75 > μM meperidine, and r = 0.89, p < 0.0001 at 350 μM meperidine, n = 21) and CYP3A4-selective midazolam 1′-hydroxylation ( r = 0.59, p < 0.01 at 75 μM meperidine, and r = 0.55, p < 0.01 at 350 μM meperidine, n = 23). No significant correlation was observed with CYP2C19-selective S -mephenytoin 4′-hydroxylation ( r = 0.36, p = 0.2 at 75 μM meperidine, and r = 0.02, p = 0.9 at 350 μM meperidine, n = 13). An anti-CYP2B6 antibody inhibited normeperidine formation by 46%. In contrast, antibodies inhibitory to CYP3A4 and CYP2C8/9/18/19 had little effect (<14% inhibition). Experiments with thiotepa and ketoconazole suggested inhibition of microsomal CYP2B6 and CYP3A4 activity, whereas studies with fluvoxamine (a substrate of CYP2C19) were inconclusive due to lack of specificity. We conclude that normeperidine formation in human liver microsomes is mainly catalyzed by CYP2B6 and CYP3A4, with a minor contribution from CYP2C19. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drug Metabolism and Disposition Am. Soc for Pharma & Experimental Therapeutics

CYP2B6, CYP3A4, AND CYP2C19 ARE RESPONSIBLE FOR THE IN VITRO N-DEMETHYLATION OF MEPERIDINE IN HUMAN LIVER MICROSOMES

CYP2B6, CYP3A4, AND CYP2C19 ARE RESPONSIBLE FOR THE IN VITRO N-DEMETHYLATION OF MEPERIDINE IN HUMAN LIVER MICROSOMES

Drug Metabolism and Disposition , Volume 32 (9): 930 – Sep 1, 2004

Abstract

Abstract Meperidine is an opioid analgesic metabolized in the liver by N -demethylation to normeperidine, a potent stimulant of the central nervous system. The purpose of this study was to identify the human cytochrome P450 (P450) enzymes involved in normeperidine formation. Our in vitro studies included 1) screening 16 expressed P450s for normeperidine formation, 2) kinetic experiments on human liver microsomes and candidate P450s, and 3) correlation and inhibition experiments using human hepatic microsomes. After normalization by its relative abundance in human liver microsomes, CYP2B6, CYP3A4, and CYP2C19 accounted for 57, 28, and 15% of the total intrinsic clearance of meperidine. CYP3A5 and CYP2D6 contributed to < 1%. Formation of normeperidine significantly correlated with CYP2B6-selective S -mephenytoin N -demethylation ( r = 0.88, p < 0.0001 at 75 > μM meperidine, and r = 0.89, p < 0.0001 at 350 μM meperidine, n = 21) and CYP3A4-selective midazolam 1′-hydroxylation ( r = 0.59, p < 0.01 at 75 μM meperidine, and r = 0.55, p < 0.01 at 350 μM meperidine, n = 23). No significant correlation was observed with CYP2C19-selective S -mephenytoin 4′-hydroxylation ( r = 0.36, p = 0.2 at 75 μM meperidine, and r = 0.02, p = 0.9 at 350 μM meperidine, n = 13). An anti-CYP2B6 antibody inhibited normeperidine formation by 46%. In contrast, antibodies inhibitory to CYP3A4 and CYP2C8/9/18/19 had little effect (<14% inhibition). Experiments with thiotepa and ketoconazole suggested inhibition of microsomal CYP2B6 and CYP3A4 activity, whereas studies with fluvoxamine (a substrate of CYP2C19) were inconclusive due to lack of specificity. We conclude that normeperidine formation in human liver microsomes is mainly catalyzed by CYP2B6 and CYP3A4, with a minor contribution from CYP2C19.

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Publisher
Am. Soc for Pharma & Experimental Therapeutics
Copyright
Copyright © Drug Metabolism and Disposition
ISSN
0090-9556
eISSN
1521-009X
Publisher site

Abstract

Abstract Meperidine is an opioid analgesic metabolized in the liver by N -demethylation to normeperidine, a potent stimulant of the central nervous system. The purpose of this study was to identify the human cytochrome P450 (P450) enzymes involved in normeperidine formation. Our in vitro studies included 1) screening 16 expressed P450s for normeperidine formation, 2) kinetic experiments on human liver microsomes and candidate P450s, and 3) correlation and inhibition experiments using human hepatic microsomes. After normalization by its relative abundance in human liver microsomes, CYP2B6, CYP3A4, and CYP2C19 accounted for 57, 28, and 15% of the total intrinsic clearance of meperidine. CYP3A5 and CYP2D6 contributed to < 1%. Formation of normeperidine significantly correlated with CYP2B6-selective S -mephenytoin N -demethylation ( r = 0.88, p < 0.0001 at 75 > μM meperidine, and r = 0.89, p < 0.0001 at 350 μM meperidine, n = 21) and CYP3A4-selective midazolam 1′-hydroxylation ( r = 0.59, p < 0.01 at 75 μM meperidine, and r = 0.55, p < 0.01 at 350 μM meperidine, n = 23). No significant correlation was observed with CYP2C19-selective S -mephenytoin 4′-hydroxylation ( r = 0.36, p = 0.2 at 75 μM meperidine, and r = 0.02, p = 0.9 at 350 μM meperidine, n = 13). An anti-CYP2B6 antibody inhibited normeperidine formation by 46%. In contrast, antibodies inhibitory to CYP3A4 and CYP2C8/9/18/19 had little effect (<14% inhibition). Experiments with thiotepa and ketoconazole suggested inhibition of microsomal CYP2B6 and CYP3A4 activity, whereas studies with fluvoxamine (a substrate of CYP2C19) were inconclusive due to lack of specificity. We conclude that normeperidine formation in human liver microsomes is mainly catalyzed by CYP2B6 and CYP3A4, with a minor contribution from CYP2C19.

Journal

Drug Metabolism and DispositionAm. Soc for Pharma & Experimental Therapeutics

Published: Sep 1, 2004

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