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https://hdl.handle.net/2440/14339
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Type: | Journal article |
Title: | Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. |
Author: | Kirkwood, L. Nation, R. Somogyi, A. |
Citation: | British Journal of Clinical Pharmacology, 1997; 44(6):549-555 |
Publisher: | BLACKWELL SCIENCE LTD |
Issue Date: | 1997 |
ISSN: | 0306-5251 1365-2125 |
Abstract: | <h4>Aims</h4>Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated.<h4>Methods</h4>The kinetics of formation of N- and O-demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.<h4>Results</h4>Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N-demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N-demethylation in both extensive and poor metabolizers. The CYP3A inducer, alpha-naphthoflavone, increased N-demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar Km values. The kinetic constants for O-demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O-demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.<h4>Conclusions</h4>CYP2D6 is the major enzyme mediating O-demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. |
Keywords: | Microsomes, Liver Humans Codeine Cytochrome P-450 Enzyme System Aryl Hydrocarbon Hydroxylases Cytochrome P-450 CYP2D6 Oxidoreductases, N-Demethylating Analgesics, Opioid Antibodies, Blocking Enzyme Inhibitors Enzyme Induction Dealkylation Biotransformation Kinetics Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 CYP2D6 Inhibitors |
DOI: | 10.1046/j.1365-2125.1997.t01-1-00626.x |
Published version: | http://dx.doi.org/10.1046/j.1365-2125.1997.t01-1-00626.x |
Appears in Collections: | Aurora harvest 2 Pharmacology publications |
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