Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance

The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameter...

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Veröffentlicht in:European journal of pharmaceutical sciences 2017-04, Vol.101, p.80-89
Hauptverfasser: Palacharla, Raghava Choudary, Uthukam, Venkatesham, Manoharan, Arunkumar, Ponnamaneni, Ranjith Kumar, Padala, Nagasurya Prakash, Boggavarapu, Rajesh Kumar, Bhyrapuneni, Gopinadh, Ajjala, Devender Reddy, Nirogi, Ramakrishna
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container_title European journal of pharmaceutical sciences
container_volume 101
creator Palacharla, Raghava Choudary
Uthukam, Venkatesham
Manoharan, Arunkumar
Ponnamaneni, Ranjith Kumar
Padala, Nagasurya Prakash
Boggavarapu, Rajesh Kumar
Bhyrapuneni, Gopinadh
Ajjala, Devender Reddy
Nirogi, Ramakrishna
description The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities. The addition of 0.1% BSA in the incubation markedly improved the unbound intrinsic clearance values of probe substrates by reducing the Km values with little or no effect on maximal velocity. The addition of BSA (0.1 and 1.0% w/v) did not influence the unbound intrinsic clearance of marker reactions for CYP2A6, and CYP3A4 enzymes. The addition of 0.1% w/v BSA is sufficient to determine the intrinsic clearance of marker probe reactions by metabolite formation approach. The predicted hepatic clearance values for the substrates using the well-stirred model, in the presence of BSA (0.1% BSA), are comparable to the in vivo hepatic clearance values. [Display omitted]
doi_str_mv 10.1016/j.ejps.2017.01.027
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The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities. The addition of 0.1% BSA in the incubation markedly improved the unbound intrinsic clearance values of probe substrates by reducing the Km values with little or no effect on maximal velocity. The addition of BSA (0.1 and 1.0% w/v) did not influence the unbound intrinsic clearance of marker reactions for CYP2A6, and CYP3A4 enzymes. The addition of 0.1% w/v BSA is sufficient to determine the intrinsic clearance of marker probe reactions by metabolite formation approach. The predicted hepatic clearance values for the substrates using the well-stirred model, in the presence of BSA (0.1% BSA), are comparable to the in vivo hepatic clearance values. 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source MEDLINE; Access via ScienceDirect (Elsevier)
subjects Bovine serum albumin (BSA)
CYP450 enzymes
Cytochrome P-450 Enzyme Inhibitors - pharmacology
Cytochrome P-450 Enzyme System - metabolism
Enzyme inhibition
Fatty acids
Fatty Acids - pharmacology
Fatty Acids, Unsaturated - pharmacology
Hepatic clearance
Humans
In vitro – In vivo extrapolation (IVIVE)
Intrinsic clearance
Kinetics
Liver - drug effects
Liver - metabolism
Michaelis-Menten kinetics
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Serum Albumin, Bovine - metabolism
Well-stirred model
title Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance
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