paliperidone is the primary active metabolite of the older antipsychotic risperidone.1 a previous study of paliperidone showed that no metabolites were detected in plasma and that renal excretion was the major route of elimination , with 59% of the nonmetabolized dose excreted in urine.2 therefore , it is unlikely that paliperidone is metabolized in the body and that paliperidone distribution is influenced by other drugs . in the case presented in this report , the authors observed a patient who experienced worsening psychotic symptoms after switching from risperidone to paliperidone extended - release tablets while he was also receiving ts-1 ( taiho pharmaceutical co , ltd , tokyo , japan ) , an oral anticancer drug containing a 5-fluorouracil derivative.3 the patient in this case was a 39-year - old man with a 15-year history of schizophrenia . his mental condition was maintained for several years with a dose of 24 mg / day of risperidone . his positive and negative syndrome scale ( panss ) scores ranged from 42 to 50 . additionally , he suffered from colon cancer and had received a sigmoid colon resection at age 34 , as well as undergoing treatment with the anticancer agent ts-1 ( 100 mg daily over 6-week intervals  that is , ts-1 treatment for 4 weeks and cessation of medication for 2 weeks ) . ts-1 is a novel oral anticancer agent comprising tegafur , a prodrug of 5-fluorouracil ( 5-fu ) , and two modulators.3 one observed side effect of the ts-1 medication was mild to moderate diarrhea ( grade 23 ) , which disappeared during the cessation of ts-1 . the patient gave his written informed consent to participate in this switching study , and the patient s usual treatment of 2 mg / day of risperidone was changed to 3 mg / day of paliperidone extended - release tablets . the authors assumed that the equivalent dose ratio of paliperidone should be 1:2 ( 4 mg / day ) , but the only available paliperidone extended - release tablet was in a 3 mg dose . three months after switching to paliperidone extended - release tablets , the patient s mental condition gradually deteriorated with the development of auditory hallucinations , persecution mania , and self - talking , and his panss score was 94 . the patient s dose was increased to 6 mg / day but his mental condition remained unchanged ( panss score of 82 ) . the dose was then increased to 12 mg / day and after this there was no evidence of psychotic symptoms . the patient s mental condition was maintained over 12 months with 12 mg / day without any adverse effects , and his panss scores ranged from 44 to 52 ( figure 1 ) . an analysis of the plasma drug concentrations showed that with 2 mg / day of risperidone , the patient s risperidone plasma levels were less than 0.5 ng / ml , and his paliperidone plasma levels ranged between 21.3 and 22.9 ng / ml . table 1 and figure 1 show the patient s paliperidone plasma concentrations at various doses both with and without ts-1 after beginning the paliperidone extended - release tablet regimen . the concentration - to - dose ratio of paliperidone during the ts-1 treatment was 1.55  0.34 , and the concentration - to - dose ratio of paliperidone without ts-1 treatment was 3.21  0.46 ( table 1 ) . this case suggests there is a drug  drug interaction between paliperidone extended - release tablets and ts-1 ; this is based on the observed clinical symptoms and the fluctuation of the paliperidone concentration - to - dose ratio ( table 1 ) . this case report is the first to indicate a drug  drug interaction between paliperidone extended - release tablets and ts-1 . the use of a standard drug interaction tool such as hansten and horn4 is strongly recommended when identifying drug interactions ; however , there is no information available about this particular interaction in the hansen / horn tool because this tool has a slight bias against newly reported drug interactions . the bioavailability of paliperidone ( 28% ) is lower than that of risperidone ( 70%).1 the time to peak concentration of paliperidone and risperidone is 24 and 1.5 hours , respectively.1 these differences likely explain why decreased plasma levels occurred in this case with paliperidone and not risperidone . because ts-1 induced diarrhea in this patient , it is considered that the concomitant administration of paliperidone extended - release tablets with ts-1 decreased this patient s oral bioavailability of paliperidone , which resulted in more severe psychotic symptoms . a preliminary study reported that unchanged drug represented 51.4%67.5% ( average , 59.4% ) of the administered dose , indicating that paliperidone was metabolized to only a limited extent.2 the absolute bioavailability of the instant - release formulation of paliperidone is 106%.5 these data also suggest that the metabolism of paliperidone is limited . however , minor metabolism was observed in incubates of paliperidone with heterologous organisms expressing human cyp3a4 and cyp2d6 , suggesting the possible involvement of these two cytochrome p450 ( cyp ) forms in the metabolism of paliperidone.2 on the other hand , 5-fu is metabolized by cyp2a6 and 5-fu showed little or no inhibitory effect on cyp - catalyzed reactions such as cyp1a2 , cyp2c9 , cyp2c19 , cyp2c8 , cyp2e1 , cyp2d6 , and cyp3a in human liver microsomal preparations.6 therefore , it is less likely that drug  drug interaction between 5-fu and paliperidone extended release is attributable to cyp - catalyzed reactions . paliperidone extended - release tablets use oros ( osmotic - controlled release oral delivery system ) technology . oros is a controlled - release oral drug delivery system in the form of a tablet.1 the tablet has a rigid , water - permeable jacket with one or more small , laser - drilled holes . as the tablet passes through the body , the osmotic pressure of water entering the tablet pushes the active drug through the opening in the tablet . the result is that the time to maximum plasma concentration of paliperidone extended release is approximately 24 hours , with no detection of the unchanged drug in the feces of healthy volunteers.1 several drugs such as nifedipine , hydromorphone , venlafaxine , and methylphenidate use oros technology , with the system having spread all over the world . in conclusion , this case indicates the existence of a drug  drug interaction between paliperidone extended release and ts-1 . although there is no known prevalence rate , physicians and psychiatrists should be aware of the effects that might result from administering these two drugs together .
until now there has been no information available on drug interaction between paliperidone and ts-1 , an oral anticancer drug containing a 5-fluorouracil derivative . 
 the patient in the case presented here was a 39-year - old man with a 15-year history of schizophrenia . 
 the patient s usual treatment of 2 mg / day of risperidone was changed to 3 mg / day of paliperidone extended release . 
 he experienced worsening psychotic symptoms after switching from risperidone to paliperidone while he was also receiving ts-1 . 
 retrospective analyses showed plasma concentration of paliperidone was consistently lower during the treatment with ts-1 than without ts-1 . 
 this case suggests there is drug interaction between paliperidone extended - release tablets and ts-1 .