In vitro studies on quetiapine metabolism using the substrate depletion approach with focus on drug-drug interactions

Jørgen Hasselstøm; Kristian Linnet

In vitro studies on quetiapine metabolism using the substrate depletion approach with focus on drug-drug interactions

Jørgen Hasselstøm^*, Kristian Linnet

^*Corresponding author for this work

Section of Forensic Chemistry

25 Citations (Scopus)

Abstract

The metabolism of the atypical antipsychotic quetiapine was investigated by in vitro methods. Pharmacokinetic parameters were determined in human liver microsomes and recombinant cytochrome P450 measuring substrate depletion and product formation. The cytochrome P450 isozymes CYP3A4 and CYP2D6 displayed activity towards quetiapine. The isozyme CYP2D6 played a minor role in the metabolism of quetiapine as CYP3A4 contributed 89% to the overall metabolism. A K_m value of 18 μM was determined by substrate depletion, suggesting linear kinetics under therapeutic conditions. Drugs known to inhibit CYP3A4, such as ketoconazole and nefazodone, displayed almost complete inhibition at low concentrations, whereas inhibitors of CYP2D6 do not seem to have a clinically relevant effect.

Original language	English
Journal	Drug Metabolism and Drug Interactions
Volume	21
Issue number	3-4
Pages (from-to)	187-211
Number of pages	25
ISSN	0792-5077
Publication status	Published - 6 Jul 2006

Keywords

Drug-drug interactions
Metabolism
Quetiapine
Substrate depletion

Cite this

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abstract = "The metabolism of the atypical antipsychotic quetiapine was investigated by in vitro methods. Pharmacokinetic parameters were determined in human liver microsomes and recombinant cytochrome P450 measuring substrate depletion and product formation. The cytochrome P450 isozymes CYP3A4 and CYP2D6 displayed activity towards quetiapine. The isozyme CYP2D6 played a minor role in the metabolism of quetiapine as CYP3A4 contributed 89% to the overall metabolism. A Km value of 18 μM was determined by substrate depletion, suggesting linear kinetics under therapeutic conditions. Drugs known to inhibit CYP3A4, such as ketoconazole and nefazodone, displayed almost complete inhibition at low concentrations, whereas inhibitors of CYP2D6 do not seem to have a clinically relevant effect.",

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T1 - In vitro studies on quetiapine metabolism using the substrate depletion approach with focus on drug-drug interactions

AU - Hasselstøm, Jørgen

AU - Linnet, Kristian

PY - 2006/7/6

Y1 - 2006/7/6

N2 - The metabolism of the atypical antipsychotic quetiapine was investigated by in vitro methods. Pharmacokinetic parameters were determined in human liver microsomes and recombinant cytochrome P450 measuring substrate depletion and product formation. The cytochrome P450 isozymes CYP3A4 and CYP2D6 displayed activity towards quetiapine. The isozyme CYP2D6 played a minor role in the metabolism of quetiapine as CYP3A4 contributed 89% to the overall metabolism. A Km value of 18 μM was determined by substrate depletion, suggesting linear kinetics under therapeutic conditions. Drugs known to inhibit CYP3A4, such as ketoconazole and nefazodone, displayed almost complete inhibition at low concentrations, whereas inhibitors of CYP2D6 do not seem to have a clinically relevant effect.

AB - The metabolism of the atypical antipsychotic quetiapine was investigated by in vitro methods. Pharmacokinetic parameters were determined in human liver microsomes and recombinant cytochrome P450 measuring substrate depletion and product formation. The cytochrome P450 isozymes CYP3A4 and CYP2D6 displayed activity towards quetiapine. The isozyme CYP2D6 played a minor role in the metabolism of quetiapine as CYP3A4 contributed 89% to the overall metabolism. A Km value of 18 μM was determined by substrate depletion, suggesting linear kinetics under therapeutic conditions. Drugs known to inhibit CYP3A4, such as ketoconazole and nefazodone, displayed almost complete inhibition at low concentrations, whereas inhibitors of CYP2D6 do not seem to have a clinically relevant effect.

KW - Drug-drug interactions

KW - Metabolism

KW - Quetiapine

KW - Substrate depletion

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M3 - Journal article

C2 - 16841513

AN - SCOPUS:33745668220

SN - 2363-8907

VL - 21

SP - 187

EP - 211

JO - Drug Metabolism and Drug Interactions

JF - Drug Metabolism and Drug Interactions

IS - 3-4

ER -

In vitro studies on quetiapine metabolism using the substrate depletion approach with focus on drug-drug interactions

Abstract

Keywords

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