Universität zu Köln

Abduljalil, K., Frank, D., Gaedigk, A., Klaassen, T., Tomalik-Scharte, D., Jetter, A., Jaehde, U., Kirchheiner, J. and Fuhr, U. (2010). Assessment of Activity Levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 Genes by Population Pharmacokinetics of Dextromethorphan. Clin. Pharmacol. Ther., 88 (5). S. 643 - 652. NEW YORK: NATURE PUBLISHING GROUP. ISSN 0009-9236

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Abstract

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30 mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020 l/h), whereas the metabolic activity of CYP2D6*41 was very low (85 l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These results refine genotype-based predictions of pharmacokinetics for DM and presumably for other CYP2D6 substrates as well.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Abduljalil, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frank, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaedigk, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaassen, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tomalik-Scharte, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jetter, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaehde, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirchheiner, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-493088
DOI:	10.1038/clpt.2010.137
Journal or Publication Title:	Clin. Pharmacol. Ther.
Volume:	88
Number:	5
Page Range:	S. 643 - 652
Date:	2010
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	NEW YORK
ISSN:	0009-9236
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYP2D6 ACTIVITY; HUMAN VOLUNTEERS; INTERMEDIATE METABOLIZERS; CYTOCHROME-P450 2D6.1; PHENOTYPE; DEXTRORPHAN; HUMANS; POLYMORPHISM; DUPLICATION; CYP2C19 Multiple languages Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49308