Influence of CYP3A metabolizer status on the pharmacokinetics and pharmacodynamics of amiodarone.
The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status.


METHODS
12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6 beta-hydroxycortisol (6 beta-OHC and the ratio of 6 beta-hydroxycortisol to urinary free cortisol (6 beta-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 +/- 11 days (2nd period) and after 182 +/- 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 +/- 11 days (during the second period).


RESULTS
Both the 6 beta-OHC excretion and 6 beta-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6 beta-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6 beta-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics.


CONCLUSIONS
This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.
Micuda
S
S
Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Králové. micuda@lfhk.cuni.cz
Hodac
M
M
Parízek
P
P
Pleskot
M
M
Sispera
L
L
Cerman
J
J
Maláková
J
J
Martínková
J
J
Pidrman
V
V
D000328:Adult; D000368:Aged; D000638:Amiodarone / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D022062:Electrophysiologic Techniques, Cardiac; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000638:Amiodarone; D006854:Hydrocortisone