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Genetically determined oxidation capacity and the disposition of debrisoquine.
Author(s) -
Sloan TP,
Lancaster R,
Shah RR,
Idle JR,
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.tb01528.x
Subject(s) - debrisoquine , urine , chemistry , pharmacokinetics , oral administration , hydroxylation , pharmacogenetics , pharmacology , medicine , metabolism , biology , cyp2d6 , biochemistry , enzyme , genotype , cytochrome p450 , gene
1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the ‘extensive metabolizer’ (EM; n = 5) and ‘poor metabolizer’ (PM; n = 5) phenotypes. The 4‐ hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity‐limited and displayed significant dose‐dependency over a range of 1‐20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first‐order kinetics over a dose range of 10‐40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post‐dosing, and higher values for areas under the plasma concentration‐time curve (EM: 105.6 +/‐ 7.0 ng ml‐1 h; PM: 371.4 +/‐ 22.4 ng ml‐1 h, 2P less than 0.0001), neither debrisoquine plasma half‐ life (EM: 3.0 +/‐ 0.5 h; PM: 3.3 +/‐ 0.4 h) nor renal clearance of the drug (EM: 152.8 +/‐ 30.3 ml min‐1; PM: 137 +/‐ 4.5 ml min‐1) displayed significant inter‐phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a ‘metabolic ratio’ derived from a single 0‐8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre‐systemic elimination capacity.