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  • Title: The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition.
    Author: Devonshire HW, Kong I, Cooper M, Sloan TP, Idle JR, Smith RL.
    Journal: Br J Clin Pharmacol; 1983 Aug; 16(2):157-66. PubMed ID: 6615690.
    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.
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