The contribution of genetically determined oxidation status to inter‐ individual variation in phenacetin disposition.

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Abstract
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.