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Type: Journal article
Title: Determination of the 4-monohydroxy metabolites of perhexiline in human plasma, urine and liver microsomes by liquid chromatography
Author: Davies, B.
Herbert, M.
Coller, J.
Somogyi, A.
Milne, R.
Sallustio, B.
Citation: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 2006; 843(2):302-309
Publisher: Elsevier Science BV
Issue Date: 2006
ISSN: 1570-0232
Statement of
Benjamin J. Davies, Megan K. Herbert, Janet K. Coller, Andrew A. Somogyi, Robert W. Milne and Benedetta C. Sallustio
Abstract: The use of perhexiline (PHX) is limited by hepatic and neurological toxicity associated with elevated concentrations in plasma that are the result of polymorphism of the cytochrome P450 2D6 isoform (CYP2D6). PHX is cleared by hepatic oxidation that produces three 4-monohydroxy metabolites: cis-OH-PHX, trans1-OH-PHX and trans2-OH-PHX. The current study describes an HPLC-fluorescent method utilising pre-column derivatization with dansyl chloride. Following derivatization, the metabolites were resolved on a C18 column with a gradient elution using a mobile phase composed of methanol and water. The method described is suitable for the quantification of the metabolites in human plasma and urine following clinical doses and for kinetic studies using human liver microsomes. The method demonstrates sufficient sensitivity, accuracy and precision between 5.0 and 0.01, 50.0 and 0.2 and 1.0 and 0.005 mg/l in human plasma, urine and liver microsomes, respectively, with intra-assay coefficients of variation and bias <15%, except at the lowest limit of quantification (<20%). The inter-assay coefficients of variation and bias were <15%. The application of this method to plasma and urine samples of five CYP2D6 extensive metaboliser (EM) patients at steady state with respect to PHX dosing determined that the mean (±S.D.) renal clearances of trans1-OH-PHX and cis-OH-PHX were 1.58 ± 0.35 and 0.16 ± 0.06 l/h, respectively. The mean (±S.D.) dose recovered in urine as free and glucuronidated 4-monohydroxy PHX metabolites was 20.6 ± 11.6%.
Keywords: HPLC
liver microsomes
DOI: 10.1016/j.jchromb.2006.06.020
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Pharmacology publications

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