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The contribution of genetically determined oxidation status to inter‐ individual variation in phenacetin disposition.
Author(s) -
Devonshire HW,
Kong I.,
Cooper M.,
Sloan TP,
Idle J.R.,
Smith RL
Publication year - 1983
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1983.tb04980.x
Subject(s) - phenacetin , debrisoquine , hydroxylation , chemistry , urine , microsome , pharmacology , metabolism , biochemistry , chromatography , biology , in vitro , enzyme , cytochrome p450 , cyp2d6
The oxidative O‐de‐ethylation and aromatic 2‐hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. The EM group excreted in the urine significantly more paracetamol (EM: 40.8 +/‐ 14.9% dose/0‐8 h; PM: 29.2 +/‐ 8.7% dose/0‐8 h, 2P less than 0.05) and significantly less 2‐hydroxylated metabolites (EM: 4.7 +/‐ 2.3% dose/0‐ 8 h; PM: 9.7 +/‐ 3.5% dose/0‐8 h, 2P less than 0.005) than the PM group. Apparent first‐order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (kml) were higher in the EM group (EM: k = 0.191 +/‐ 0.151 h‐1; kml = 0.091 +/‐ 0.025 h‐1; PM: k = 0.098 +/‐ 0.035 h‐1, 2P less than 0.05, kml = 0.052 +/‐ 0.019 h‐1, 2P less than 0.05) than the PM group. The apparent first‐order rate constant for 2‐hydroxylation displayed no significant inter‐phenotype differences. Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter‐individual variability in phenacetin disposition encountered in this study.