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Influence of CYP2D6 activity on
the disposition and cardiovascular toxicity of the antidepressant agent
venlafaxine in humans.
Lessard E, Yessine MA,
Hamelin BA, O'Hara G, LeBlanc J, Turgeon J.
Institute, Laval Hospital, Ste-Foy, Canada.
According to in-vitro
studies with microsomes from human livers and from yeast expression
systems with high CYP2D6 activity, the major oxidation pathway of
venlafaxine is catalysed by CYP2D6. In this study, we investigated the
role of the CYP2D6 polymorphism and the effects of low-dose quinidine, a
selective inhibitor of, CYP2D6, on the disposition of venlafaxine.
Fourteen healthy men, eight with the extensive metabolizer and six with
the poor metabolizer phenotype were administered venlafaxine
hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1
week apart); once alone and once during the concomitant administration
of quinidine sulfate 100 mg every 12 h. Blood and urine samples were
collected under steady-state conditions over one dosing interval (12 h).
When venlafaxine was administered alone, the oral clearance of
venlafaxine was more than fourfold less in poor metabolizers compared to
extensive metabolizers (P < 0.05). This was mainly due to a decreased
capability of poor metabolizers to form O-desmethylated metabolites at
the position 4 of the aromatic moiety. In extensive metabolizers,
quinidine decreased venlafaxine oral clearance from 100 +/- 62 l/h to 17
+/- 5 l/h (mean +/- SD; P < 0.05) without any effects on renal
clearance (4 +/- 1 l/h during venlafaxine alone and 4 +/- 1 l/h during
venlafaxine plus quinidine). In these individuals, the sequential
metabolism of venlafaxine to O-desmethylvenlafaxine and to
N,O-didesmethylvenlafaxine was inhibited by quinidine coadministration
so that metabolic clearances to O-desmethylated metabolites decreased
from 43 +/- 32 l/h to 2 +/- 1 l/h (P < 0.05). In poor metabolizers,
coadministration of quinidine did not cause significant changes in oral
clearance and partial metabolic clearances of venlafaxine to its various
metabolites. Decreased CYP2D6 activity could also be associated with
cardiovascular toxicity as observed in four patients during treatment
with the drug. Thus, genetically determined or pharmacologically altered
CYP2D6 activity represents a major determinant of venlafaxine
disposition in humans.
PMID: 10780263 [PubMed - indexed for