Effect of fluvoxamine on the pharmacokinetics of quinidine.
OBJECTIVE
To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine.


METHODS
This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied.


RESULTS
The results showed a statistically significant median reduction of 2944% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine.


CONCLUSIONS
The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P4503A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine.
Damkier
P
P
Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense University. p-damkier@cekfo.sdu.dk
Hansen
L L
LL
Brøsen
K
K
D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D016666:Fluvoxamine / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C013569:3-hydroxyquinidine; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D039181:Steroid 16-alpha-Hydroxylase; D011802:Quinidine; D016666:Fluvoxamine