the antiepileptic agent phenytoin ( pht ) has a narrow range of effective blood concentrations and nonlinearity pharmacokinetics .
therefore , the monitoring of its blood concentration ( therapeutic drug monitoring , tdm ) is essential for ensuring a proper dosage and successful treatment .
because pht is primarily metabolized by the enzymes cytochrome p450 ( cyp ) 2c9 and cyp2c19 , caution must be taken with regard to the fluctuations of the blood levels of pht when administered in combination with other medications that induce or inhibit these enzymes .
for example combination therapy with fluoropyrimidine anticancer drugs and pht are known to increase the blood levels of pht and the risk of intoxication [ 3 , 4 , 5 , 6 ] .
the compound drug s-1 , composed of a combination of tegafur - gimeracil - oteracil potassium , is no exception , and , in japan , there have recently been a number of reports on drug interactions due to the combined use of s-1 and pht [ 7 , 8 ] . in these cases
also , the s-1 treatment schedule , including periods of daily administration and interrupted by periods of rest , complicates the interpretation of its interaction with pht . in at least 1 case ,
the elevated blood levels of pht persisted even after the oral administration of s-1 had ceased , indicating that caution is also needed during the s-1 rest period .
unfortunately , reports on the long - term monitoring of the variations in the blood levels of pht during the combined s-1 and pht treatment and a thorough understanding of their interaction are lacking .
the objective of this study was to describe the interactive effects of pht and s-1 using long - term therapeutic drug monitoring of pht . through regular
monitoring of blood levels of pht , we were able to conduct a pharmacokinetic analysis and describe the nature of interaction between these 2 drugs .
the patient was a 72-year - old man with a height of 157.2 cm , a body weight of 54.3 kg , and a body surface area of 1.535 m. he had been continuously treated with orally administered pht 130 mg / day ( 1.3 g / day of aleviatin 10% powder ) for more than 20 years to prevent symptomatic epilepsy ; he had never had a seizure during this time . in march 2010
, he complained of upper abdominal discomfort , underwent an endoscopic examination of the upper digestive tract , and was diagnosed with gastric cancer .
a pylorogastrectomy was performed at the department of digestive surgery , fukui university hospital , and on june 9 , 2010 , he began outpatient postoperative chemotherapy with an oral administration of s-1 ( 80 mg / day ) .
one course of treatment consisted of a 28-day period of medication and a 14-day off - drug period . during chemotherapy treatment ,
the patient continued taking other prescribed medication ( pravastatin sodium , magnesium oxide , digestive enzyme complexes , itopride and sennoside ) .
samples of the patient 's blood were taken at every consultation and used to monitor changes in blood concentrations of pht during the course of s-1 chemotherapy .
after obtaining the patient 's informed consent , pht concentrations were measured using an automated immunoassay .
the initial concentration ( prior to s-1 administration of pht ) was 6.0 g / ml . the pht concentration had not increased at day 14 , but on day 28 , an increase was observed ; by day 84 ( day 14 of rest , during the second course of treatment ) , pht had surpassed the toxic level ( 20 g / ml ; 22.9 g / ml ) . at this time ,
the patient complained of light - headedness and falls , but the third course of treatment was started without reducing the pht dosage , and the blood concentration of pht remained at a toxic level ( 24.1 g / ml at day 10 of rest during the third course of treatment , and 23.7 g / ml at day 14 of rest during the third course of treatment ) .
the samples were also analyzed to determine blood counts and bioindicators of liver and kidney function ( total bilirubin , aspartate and alanine aminotransferase , serum creatinine , and serum albumin ) .
initial values were as follows : total bilirubin 0.4 mg / dl , aspartate aminotransferase 15 iu / l , alanine aminotransferase 11 iu / l , serum creatinine 0.81 mg / dl and serum albumin 4.0 g / dl .
changes in these values were not associated with variations in the blood levels of pht .
regarding symptoms , falls continued , and at the beginning of the fourth course of treatment , the doses of pht were reduced from 130 mg / day to 100 mg / day . as a result , at day 7 of rest during the fourth course of treatment , the blood levels of pht decreased to 10.4 g / ml , and the symptoms ceased .
while the blood concentrations of pht continued to fluctuate after the dosage was reduced to 100 mg / day and remained higher than those found before the initiation of s-1 therapy , they never reached toxic levels .
however , the sixth course of the treatment was postponed for 2 weeks due to leukopenia . as a result ,
the blood concentration of pht on the day before the initiation of the sixth course was 4.0 g / ml , lower than the effective blood concentration . because the blood concentration was low , physicians increased the dosage of pht to 130 mg / day
. the concentration of pht at the start of the seventh course was not measured , but the symptoms of light - headedness and falls returned .
thereafter , the dosage of pht was not modified again , but the blood concentration of pht decreased to 10.8 g / ml at day 15 of the seventh course of treatment .
while a number of reports on the drug interactions between pht and fluoropyrimidine drugs have already been published , most of them reported having performed a tdm after the appearance of symptoms of intoxication with pht .
also , there have been few reports on the monitoring of the blood concentrations of pht from the time of the initiation of the combined treatment . here , we performed tdm from the initiation of s-1 treatment .
although the blood levels of pht were found to increase after the initiation of the combined treatment , the concentrations of pht varied in a complicated manner within the effective levels . as a result , it became difficult to determine when to reduce the dosage of pht or to discontinue its administration , and consequently , the patient developed symptoms of intoxication .
however , the results provided insights into the nature of the interaction , with regards to the timing of the increase and the decrease in the blood levels of pht as well as the schedule of s-1 administration . besides s-1
liver function , renal function , and serum albumin levels have been cited as factors affecting the blood levels of pht [ 9 , 10 ] , but these do not appear to be responsible for elevated pht levels in our patient as bioindicators ( liver function  total bilirubin , aspartate and alanine aminotransferase ; renal function  serum creatinine and serum albumin ) of these 3 factors .
therefore , the increase in the blood levels of pht found here was considered to be a result of interactions between s-1 and pht .
although the mechanism of interaction between pht and fluoropyrimidine drugs , such as s-1 , remain unclear , in vitro studies using human liver microsomal fractions have shown that 5-fu , a metabolite of tegafur , does not directly impair the metabolism of pht . meanwhile , in rats , the administration of 5-fu for several consecutive days has been shown to result in decreased expression and activity of cyp2c11 , the equivalent of the human cyp2c9 [ 12 , 13 ] .
in addition , gunes et al .   reported that cyp2c9 activity decreased in patients treated with 5-fu .
based on these results , the interaction between pht and fluoropyrimidine drugs appear to involve an indirect inhibition of pht metabolism . in our study , the patient 's blood concentrations of pht reached toxic levels at day 84 after the initiation of s-1 therapy .
this is longer than the time required to reach similar levels in previous cases [ 7 , 8 ] .
however , the increase in the blood concentrations of pht had started at day 28 . in most cases involving
interactions between pht and s-1 , symptoms of pht toxicity have occurred 4 weeks after the initiation of the combined treatment , and , even in cases where the toxic symptoms developed after a longer period of time , the increases in blood levels of pht were first observed at 4 weeks .
the results of this study demonstrate that elevated blood levels of pht persisted for approximately 2 weeks after the administration of s-1 ceased . at day 42 of this study ( the 14th day of an s-1 rest period ) , the blood levels of pht were even higher than during the previous period of s-1 administration .
however , during a 28-day rest from s-1 therapy , in the fifth course of treatment , the blood levels of pht were lower than those measured during the fifth course of s-1 administration ; the low concentrations persisted even at day 10 of the sixth course of treatment .
these results suggest that with prolonged rest ( i.e. , the 4 weeks of rest experienced here ) from s-1 treatment , cyp enzymes may be restored to their original levels .
these results are similar to a case of interaction between pht and capecitabine ( a fluoropyrimidine drug like s-1 ) . in this study ,
the effects of capecitabine on the blood concentration of pht persisted until day 15 after capecitabine therapy ceased , but the inhibitory effect then disappeared in a time - dependent manner .
the above suggest that it takes more than 2 weeks until the effect of s-1 is manifested in the form of variations in the blood concentrations of pht , and that , when s-1 is administered for 4 weeks , the drug interaction persists for at least 2 weeks after cessation of treatment .
in addition , the interaction disappears or decreases to negligible levels at 4 weeks after cessation of the oral administration of s-1 . due to the complex interaction between pht and s-1 ,
determining the proper dosage of and establishing a treatment schedule for pht is a challenge .
because pht has a nonlinear pharmacokinetic behavior , its blood concentration can experience a rapid increase under the influence of s-1 .
however , if the administration of s-1 must be suspended for an extended period due to side effects such as leukopenia , the effect of s-1 on the metabolism of pht will disappear , and the pht dosage may become insufficient to maintain effective levels . therefore , when s-1 and pht are used in combination with each other , it would be preferable that pht be replaced with another antiepileptic agent that is not a substrate of cyp2c9 . in cases
where s-1 and pht must be used in combination , the possible occurrence of delayed interactions as well as the occurrence of a time lag between the period of combined administration of the drugs and the variations in the blood levels of pht , need to be taken into consideration ; tdm needs to be performed on a regular basis from the time of initiation of the combined treatment , and the doses of pht need to be adjusted accordingly .
there is no conflict of interest that may arise and affect the interpretation of this case report .
 although combination therapy with the oral fluoropyrimidine anticancer drug s-1 and the anticonvulsant phenytoin ( pht ) is known to increase blood levels of pht and the risk of intoxication , reports on long - term monitoring of blood levels of pht during combined s-1 and pht treatment and a thorough understanding of their interaction are lacking . 
 this report aims to describe interactive effects of s-1 and pht through long - term therapeutic drug monitoring of pht . 
 a 72-year - old male had been prescribed oral pht ( 130 mg / day ) for over 20 years and started receiving s-1 therapy ( 80 mg / day for 4 weeks , followed by a 2-week rest ) as postoperative adjuvant chemotherapy for gastric cancer . 
 the blood pht level was continuously monitored . prior to receiving s-1 , 
 the patient 's blood pht concentration was 6.0 g / ml , but it increased during s-1 therapy , reaching 22.9 g / ml on day 84 ( during a rest period of second cycle s-1 therapy ) . after reducing his pht dosage to 100 mg / day , it never reached toxic levels ( 4.010.4 g / ml ) . 
 it was difficult to keep blood pht concentrations constant because of the time lag between the period of combined use of s-1 and pht and the timing of manifestation and disappearance of the drug interaction . 
 the dips probability scale indicated a highly probable interaction between s-1 and pht . 
 we conclude that , when s-1 and pht are used concurrently , occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe pht concentration . 
Introduction
Case Report
Discussion
Disclosure Statement