Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports.
OBJECTIVE
We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo).


METHODS
The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable".


CONCLUSIONS
The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone.


CONCLUSIONS
It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.
Department of Pharmacy Kumamoto City Hospital, The University of Tokyo, Japan.
F
F
Yamamuro
A
A
Miki
G
G
Kondo
T
T
Maeda
H
H
Satoh
S
S
Hori
Y
Y
Sawada
D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000494:pharmacology*; D011517:Prothrombin Time; D005641:Tegafur / Q000494:pharmacology*; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D014859:Warfarin; D010094:Oxonic Acid