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Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.
Author(s) -
Speirs CJ,
Murray S,
Boobis AR,
Seddon CE,
Davies DS
Publication year - 1986
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.1365-2125.1986.tb02969.x
Subject(s) - debrisoquine , quinidine , hydroxylation , mephenytoin , pharmacology , chemistry , microsome , metabolism , biology , cyp2d6 , biochemistry , cytochrome p450 , in vitro , cyp2c19 , enzyme
Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4‐hydroxylation of debrisoquine, the O‐deethylation of phenacetin and the 1′‐hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4‐hydroxylation in vivo. Quinidine was a potent inhibitor of the 4‐hydroxylation of debrisoquine and the 1′‐hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 microM, being around 100 times more potent in this respect than quinine. Very much higher (1000‐ fold) levels of quinidine were required to inhibit the O‐deethylation of phenacetin, being rather less potent in this than quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co‐administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26‐fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4‐ hydroxylase isozyme to the elimination of the drug tested.