Significance of urinary glucaric acid measurement and its application to paclitaxel therapy.

Individual variations in P-450 activity affect the in vivo pharmacokinetics as well as the efficacy and side effect of drugs. It is proposed that urinary glucaric acid (GA) level may indirectly represent P-450 activity and may therefore be an indicator of P- 450 activity in the clinical setting. However, no standard method has been developed so far. Metabolism of paclitaxel (PTX), an anticancer drug, is mediated by P-450. If P-450 activity could be predicted by measuring urinary GA level during PTX administration and individual blood PTX concentration could be inferred, urinary GA level would be a potent tool to predict the efficacy and side effects of the drug. We therefore measured the urinary GA levels of patients on antiepileptics that are suggested to induce P-450 and those of control subjects, to determine whether urinary GA level could be an indicator of P-450 activity. Then, we examined the relationship between urinary GA level and blood PTX concentration and looked into the possibility of predicting pharmacokinetics based on the relationship between urinary GA level and area under the blood concentration-time curve (AUC). The means+/-S. D. of urinary [(GA level)/(Cr level) x 10] levels of 16 patients on antiepileptic medication and 24 control subjects were 0. 98 mg/mL+/-0. 91 and 0. 19 mg/mL+/-0. 07, respectively. The urinary GA levels of patients on antiepileptic medication were significantly higher than those of control subjects. On the other hand, the relationship between AUC and urinary GA levels in eight patients on PTX showed that AUC tended to become large when urinary GA levels were low. The above results reveal that measuring urinary GA level by the easy and noninvasive way of urine collection would enable us to predict P-450 activity and infer blood PTX concentration.

[Significance of urinary uracil measurement following administration of DPD inhibitory fluoropyrimidine(DIF)products].

Individual differences in 5-FU metabolism are mainly attributed to individual differences in the activity of DPD, an enzyme that can metabolize more than 85% of 5-FU. Because urinary uracil is a reflection of DPD activity, it is measured to predict and prevent the occurrence of side effects caused by pyrimidine-type chemotherapeutic agents. From urinary uracil values measured in 84 gastrointestinal cancer patients, 0-60 mmol/g.creatinine was set as a standard. In patients whose urinary uracil values exceeded the standard, 5-FU tended to be accumulated when S-1, a DIF product, was administered and side effects, such as anorexia, vomiting and diarrhea occurred immediately after the start of S-1 administration. If an appropriate DIF product is selected and its dosage set based on the patient's urinary uracil value, the occurrence of side effects would be reduced. Subsequently, a continuation of medication would be possible.

[Study of a relationship between a change in the urinary uracil value after a S-1 long-term administration and the recurrence of stomach cancer].

S-1 has been reported good results in the treatment of stomach cancer. However, a DPD activity change has also been reported as one of the causes for a recurrence though some recurrence cases observing a state of tumor being unchanged continuously for more than 1 year. Therefore the urinary uracil value, which could simply be predicted in the DPD activity at the time of a recurrence after having administered S-1 for a long-term, was measured. And the urinary uracil value was examined whether it could become an index of recurrence compared with a healthy 5-person example as reference. In the result, a monthly difference in change of the urinary uracil values of the reference was small. However, the urinary uracil values in patients who were administered S-1 more than 6 months but recurred, were significantly lower comparing with the healthy 5-person example. We concluded from this study that the change in DPD activity due to an induction of DPD by 5-FU and metastasis of cancer caused the recurrence and lower a urinary value. The urinary uracil value reflecting DPD activity of the whole body could be used as an index of recurrence at the time of long-term dosage of S-1. Furthermore, a measurement of the urinary uracil value seems to be promising for estimation and evaluation of the cure.