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Inter‐ and intraindividual variability of urinary dextromethorphan/dextrorphan (DM/DX) ratios in CYP2D6 extensive metabolizers (EMS) with one or two active alleles
Author(s) -
Ma J. D.,
Bertino J. S.,
Gaedigk A.,
Kashuba A. D.,
Streetman D. S.,
Nafziger A. N.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.069
Subject(s) - cyp2d6 , allele , urine , genotype , medicine , dextrorphan , dextromethorphan , biology , anesthesia , genetics , cytochrome p450 , metabolism , gene
There is significant inter‐ and intraindividual variability of urinary DM/DX ratios. Distinguishing between CYP2D6 EMs with one or two active alleles may explain a portion of the observed variability. This study evaluated DM/DX ratios in CYP2D6 EMs for 1) differences by genotype and 2) intraindividual variability. Data from four previous studies were used. 62 healthy Caucasian adults genotyped and phenotyped as CYP2D6 EMs (38.6+7.6 yrs, 19M/40F) were administered oral DM≥2 times. 12‐16 hour urine collections were assayed for DM and DX by HPLC. An unpaired t‐test was used to evaluate differences in log‐transformed DM/DX ratios by genotype. Coefficients of variation (CV%) were calculated to examine intraindividual variability of DM/DX ratios and were compared by Wilcoxon rank‐sum test. 38 subjects had 2 active alleles (*1, *2) and 21 had 1 active and 1 null allele (*3, *4, *5). 3 subjects had 1 decreased activity allele (*10) and were not included. After 30mg of oral DM, there was no difference in DM/DX ratios [geometric mean (SD)] between subjects with 2 vs 1 active allele [0.0047 (0.0105, 0.0021) vs 0.0065 (0.0180, 0.0023); p=0.23]. After repeated doses of oral DM, CV% (median, range) of DM/DX ratios were not statistically different for those with 2 (41.0%, 4.3‐136.6%) vs 1 active allele (44.5%, 6.0–105.5%) (p=0.90). Urinary DM/DX ratios cannot distinguish between CYP2D6 EMs with one or two active alleles. Clinical Pharmacology & Therapeutics (2004) 75 , P18–P18; doi: 10.1016/j.clpt.2003.11.069