The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose.
OBJECTIVE
Warfarin is a frequently used anticoagulant drug with narrow therapeutic index and high interindividual variability in the dose requirement. We have previously shown that warfarin dose is influenced by cytochrome P450 (CYP) 2C9 genotype, age, body weight and co-treatment with drugs that interfere with warfarin metabolism. As, in many patients, drug co-treatment cannot be avoided, we investigated the effect of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose.


METHODS
Caucasian patients on stable maintenance warfarin therapy with CYP2C9*1/*1 genotype (n=82) were included in the study. Plasma concentrations of (S)- and (R)-warfarin as well as warfarin hydroxylated metabolites were determined using HPLC assay and corresponding clearances of (S)- and (R)-warfarin were calculated.


RESULTS
Patients co-treated with carbamazepine (n=5) had significantly higher plasma 10-hydroxywarfarin concentrations than patients not taking any interacting drugs (n=54) (median: 0.327 microg/ml vs 0.030 microg/ml, p=0.003). (S)- and (R)-warfarin clearances were also higher in the carbamazepine co-treated group (p=0.003), as were warfarin dose requirements (median: 9.00 mg/day vs 3.86 mg/day, p=0.003). Under the conditions of this study, patients co-treated with amiodarone (n=6) did not differ significantly regarding any measured characteristic from patients with no interacting drug treatment, while patients co-treated with simvastatin or lovastatin (n=17) had lower 10-hydroxywarfarin concentration (p=0.02).


CONCLUSIONS
We confirmed important interaction between carbamazepine and warfarin metabolism which can be of major clinical importance. If treatment with carbamazepine cannot be avoided, patients taking warfarin should be frequently monitored, especially when initiating or stopping carbamazepine therapy.
Herman
Darja
D
Institute of Biochemistry, Faculty of Medicine, Ljubljana, Slovenia.
Locatelli
Igor
I
Grabnar
Iztok
I
Peternel
Polona
P
Stegnar
Mojca
M
Lainscak
Mitja
M
Mrhar
Ales
A
Breskvar
Katja
K
Dolzan
Vita
V
D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000008:administration & dosage / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010599:Pharmacokinetics; D014859:Warfarin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002220:Carbamazepine; D014859:Warfarin; C065719:10-hydroxywarfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000638:Amiodarone