Circadian variations in the pharmacokinetics of the oral anticancer agent tegafur-uracil (UFT) and its metabolites in rats.

Uracil-tegafur (UFT) is an oral anticancer drug containing uracil and 5­fluorouracil prodrug tegafur and is widely used for adjuvant chemotherapy of colorectal cancer. Although clinical data show circadian variations in plasma 5­fluorouracil concentrations during its long-term infusion, and feasibility studies of chronomodulated administration have been previously reported, the circadian pattern in plasma 5­fluorouracil concentration after UFT administrations remains unclear. The aim of this study was to identify factors causing circadian variations in UFT pharmacokinetics and estimate circadian patterns of plasma 5­fluorouracil concentration corresponding to UFT dosing time in rats. Rats were orally administered UFT (15 mg/kg as tegafur) at three different times of the day: 07:00 (23 h after light onset, HALO), 13:00 (5 HALO), or 19:00 (11 HALO), and then plasma concentrations of tegafur, 5­fluorouracil, and uracil were measured after UFT administration. We found that the area under the plasma concentration-time curves (AUC0-∞) of 5­fluorouracil depended on the UFT dosing time of day with a 2.4-fold difference between the peak (at 19:00: 13.7 ±â€¯1.4 µmol·h/L) and trough (at 13:00: 5.6 ±â€¯1.3 µmol·h/L). The simulated population mean clearance of 5­fluorouracil followed a 24-h cosine circadian curve, with the highest value in the early light phase being 2.2-fold higher than the lowest value in the early dark phase, which was an inverse circadian pattern compared to the plasma 5­fluorouracil concentration. The plasma tegafur levels suggested that circadian variation in tegafur absorption and conversion to 5­fluorouracil are factors causing variations in plasma 5­fluorouracil levels following UFT administration. In conclusion, the circadian pattern of 5­fluorouracil clearance and circadian variations in tegafur pharmacokinetics are important determinants of plasma 5­fluorouracil concentrations following UFT administration. This knowledge could help in developing a chronomodulated administration strategy of UFT for improving clinical outcomes.

Influence of metastatic disease on the usefulness of uracil pharmacokinetics as a screening tool for DPD activity in colorectal cancer patients.

PURPOSE: Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity in patients treated with a standard dose of a fluoropyrimidine such as 5-fluorouracil or capecitabine (CAP). Administration of oral uracil and subsequent measurement of uracil and dihydrouracil (DHU) plasma concentrations has been used to identify patients with DPD deficiency. Liver metastasis might influence systemic DPD activity. The aim of the study was to investigate the effect of metastatic disease on the pharmacokinetics of uracil and DHU after oral administration of uracil. METHODS: 500 mg/m(2) uracil was administered orally to 12 subjects with stages II-III colorectal cancer (CRC) who were treated in the adjuvant setting and to 12 subjects with stage IV metastasized CRC, all treated with CAP containing therapy. All subjects had a normal DPD activity defined as >6 nmol/mg/h determined in peripheral blood mononuclear cells. RESULTS: The mean uracil clearance [CL 51.7 (SD 6.4) vs. 46.7 (SD 13.0) l/h], area under the curve [AUC0-220min 20.6 (SD 6.4) vs. 21.0 (SD 5.7) h mg/l], elimination half-life [t 1/2 21 (SD 7) vs. 21 (SD 8) min], maximum concentration time [T max 27 (SD 9) vs. 25 (SD 9) min], volume of distribution [V 26.58 (SD 10.11) vs. 21.10 (SD 8.48) l] and the elimination constant [k el 2.01 (SD 0.56) vs. 2.41 (SD 0.72) h(-1)] did not differ significantly (p > 0.05) non-metastatic CRD versus metastatic CRC. CONCLUSIONS: Metastasis does not alter uracil pharmacokinetics and is similar in CRC patients with and without metastasis. Therefore, the uracil test dose could be used as a DPD phenotype test in both adjuvantly treated and metastatic CRC patients using similar cutoff criteria to identify patients with DPD deficiency.

Effects of a low-fat meal on the oral bioavailability of UFT and leucovorin in patients with colorectal cancer.

BACKGROUND: UFT is composed of tegafur, a prodrug of 5-fluorouracil, and uracil, at a fixed ratio of 1: 4. UFT is widely used with leucovorin as adjuvant chemotherapy in patients with colon cancer. As reported, UFT/leucovorin should not be taken simultaneously with food because a high fat content will reduce the systemic exposure to the active cytotoxic moiety of UFT. In this single-dose, randomized, two-way crossover study, we investigated the effects of a low-fat Japanese meal on the pharmacokinetics and oral bioavailability of UFT (2 x 100-mg capsules; dose in terms of tegafur) and leucovorin (1 x 25-mg tablet). METHODS: Patients (n = 12) were randomly assigned to receive both drugs after an overnight fast or 5 min after eating a standard Japanese breakfast (641 kcal), with a 3-day washout period between treatments. Pharmacokinetics (n = 12) were determined for tegafur, 5-fluorouracil, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). RESULTS: For 5-fluorouracil pharmacokinetics, the maximum plasma concentration and the area under the curve were reduced by 73.7% and 47.4%, respectively, when UFT was taken postprandially, and the maximum plasma concentration and the area under the curve for uracil were reduced by 84.1% and 68.9%, respectively, compared with dosing on an empty stomach. These decreases in the systemic exposure to 5-fluorouracil were quite marked and may have an impact on its antitumor effect. CONCLUSION: A low-fat meal affects the pharmacokinetics of UFT similarly to a high-fat meal.

Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes.

Takeda San Diego Inc is developing alogliptin, a small-molecule, orally available dipeptidyl peptidase IV (DPP IV) inhibitor, for the potential treatment of type 2 diabetes. In January 2008, Takeda announced that an NDA for alogliptin had been submitted to the FDA.

Effectiveness of pharmacokinetic modulating chemotherapy combined with cisplatin as induction chemotherapy in resectable locally advanced head and neck cancer: phase II study.

PURPOSE: To test the efficacy and safety of pharmacokinetic modulating chemotherapy combined with cisplatin (PMC-cisplatin) as induction chemotherapy (ICT) before definitive treatment in patients with respectable locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients with stage III-IV resectable locally advanced HNSCC were enrolled. All eligible patients received PMC-cisplatin regimen as ICT containing intravenous leucovorin 250 mg/m(2) and 5-FU 600 mg/m(2) on day 1, oral tegafur-uracil (UFUR) 250 mg/m(2)/day on days 1-5, repeated every week for six courses. Cisplatin 100 mg/m(2 )was given during the first and fourth courses of PMC. For ICT responders, concurrent chemoradiotherapy (CRT) with cisplatin/tegafur-uracil/70 Gy radiotherapy was performed. Salvage surgery plus postoperative CRT was given to ICT non-responders. RESULTS: The overall response rate of PMC-cisplatin as ICT was 76%, including a complete remission rate of 23%. The overall organ preservation rate of the multimodality treatment was 75%, with 97% in ICT responders. At a median follow-up of 25 months, 47% of the patients were still alive and disease-free. The superiority of disease-free survival was demonstrated in ICT responders. The 3-year overall survival rate was 67%. The toxicity of treatment was acceptable. CONCLUSIONS: Application of PMC-cisplatin as the induction chemotherapy before definitive treatment provides a promising result in treatment response and survival of advanced HNSCC. This regimen is effective and safe, and further studies considering the combination of PMC with other chemotherapeutics such as taxanes to improve the clinical outcome of advanced HNSCC is warranted.

Chronopharmacokinetics of oral tegafur and uracil in colorectal cancer patients.

Uracil-Ftorafur (UFT) combines the 5-fluorouracil (FU) prodrug tegafur with uracil (at a 1:4 molar ratio), which is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the limiting enzyme of FU catabolism. As a result, sustained FU concentrations are obtained in both plasma and tumor. UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic and adjuvant colorectal cancer treatment. A circadian rhythm for DPD activity has been shown in both human and animal studies, with consequences on FU plasma concentrations in patients receiving FU as a continuous infusion. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine and FU infusions, suggesting that such schedules may improve the fluoropyrimidine therapeutic index. Molecular mechanisms responsible for the circadian dependence of FU pharmacodynamics include circadian rhythms in thymidylate synthase activity and DNA synthesis, as recently reported. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.

Expression of dihydropyrimidine dehydrogenase in cancer cells but not in stromal cells predicts the efficacy of fluorouracil treatment in patients with gastric carcinoma.

BACKGROUND: It is not known whether immunohistochemical quantification of dihydropyrimidine dehydrogenase (DPD) in cancer cells, stromal mononuclear cells and normal glands predicts the efficacy of fluorouracil (FU) derivatives inpatients with T3 gastric adenocarcinoma. MATERIALS AND METHODS: The levels of DPD in cancer cells, stromal cells and normal glands were measured immunohistochemically in 111 patients with T3 gastric carcinoma. Adjuvant chemotherapy with oral UFT (uracil/tegafur[4:1]) was administered to 95 patients for more than 1 year after surgery. RESULTS: Forty-two (37.8%) patients demonstrated high DPD expression in the cytoplasm of their cancer cells. In patients with low DPD expression in cancer cells, the 5-year survival rates were 64.5% in patients given FU and 42.8% in those not given FU (p=0.014). Neither stromal cells nor normal glands affected the efficacy of FU treatment in relation to their DPD expression. CONCLUSION: DPD expression in cancer cells but not in stromal cells could be a predictor of the efficacy of FU chemotherapy in patients with T3 gastric carcinoma.

Modulation of plasma uridine concentration by 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy.

PURPOSE: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plasma uridine concentration as well as its ability to improve the bioavailability of oral uridine. PSAU is a new potent and specific inhibitor of uridine phosphorylase (Urd-Pase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. METHODS: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. RESULTS: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma uridine (2.6 +/- 0.7 microM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with uridine elevated the concentration of plasma uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (C(max)) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral uridine (7.7%) administered at 1,320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1,421 to 787 micromol/h x l and 273 micromol/h x l, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1,320 mg/kg uridine was used. CONCLUSION: The effectiveness of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.

UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer.

UFT is an oral antineoplastic drug combining uracil and tegafur in a 4:1 molar ratio. Tegafur acts as a prodrug of 5-fluorouracil (5-FU), being slowly metabolized by cytochrome P450 to 5-FU. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. At equimolar doses, higher peak plasma 5-FU concentrations are achieved with UFT plus oral leucovorin with similar systemic 5-FU exposure compared with low-dose continuous 5-FU infusions. The elimination half-life of 5-FU following UFT administration is approximately 7 h compared with 0.2 h with i.v. 5-FU. In phase II studies of UFT plus oral leucovorin for the treatment of advanced colorectal cancer, response rates ranged from 25 to 42%. UFT plus oral leucovorin is well tolerated, with manageable diarrhea being the only dose-limiting toxicity; the regimen is not associated with significant myelosuppression, mucositis, hand-foot syndrome or alopecia. UFT, with or without leucovorin, has also been evaluated alone or in combination with other cytotoxic agents for the treatment of advanced lung, breast and gastric cancers. UFT has also been evaluated as adjuvant therapy for colorectal, breast, gastric, head and neck, and superficial bladder cancers. UFT plus leucovorin offers patients an entirely oral cancer treatment, and appears to provide potential advantages over bolus 5-FU regimens with regard to toxicity and convenience of administration. These benefits should be advantageous in the adjuvant setting, as well as in advanced disease settings in which palliation is an important consideration. Ongoing clinical trials will further define the role of this promising oral treatment regimen.

[Pharmacokinetic study of UFT in cancer patients receiving maintenance dialysis].

Six post-operative cancer patients receiving chronic dialysis (4 colorectal and 2 gastric cancer) were given daily UFT (300 mg/day tid). To determine the clearance of UFT with dialysis, the plasma concentration of tegafur, 5-FU and uracil were measured on the day with dialysis and without dialysis. The plasma concentrations of tegafur at 2 hours after oral administration of UFT showed no difference between the day with dialysis and without dialysis. The concentration of 5-FU on the next day with dialysis was almost same as that of the patients with normal renal function because of the clearance of 5-FU with dialysis, although that on the 2nd day after dialysis was higher than that with dialysis. It was difficult to compare the plasma concentrations of uracil, because they are different in each patient. Therefore, it was considered to be difficult to maintain the suitable plasma concentration of uracil. However, clearance of UFT with dialysis was good and no severe side effect was observed in administration of UFT. These data suggest that UFT can be useful drug for gastrointestinal cancer patients receiving dialysis in a post-operative adjuvant chemotherapy.

[A comparative study on the serum and tissue 5-FU concentrations in patients with hepatocellular carcinoma after preoperative oral administration of UFT and 5'-DFUR].

UFT or 5'-DFUR was orally administered to the patients with hepatocellular carcinoma preoperatively and the concentrations of these drugs and 5-FU in the serum, liver tissue and cancer tissue obtained at the time of operation were measured. The unchanged 5'-DFUR was not detected in any of these samples. The concentration of 5-FU in cancer tissue was significantly higher in UFT treated group (0.409 microgram/g) than that in 5'-DFUR group (0.040 microgram/g). However, the 5-FU levels in the serum and noncancerous liver tissue were also higher than those in the patients with other organ cancers. Although UFT is a useful drug for the adjuvant chemotherapy of hepatocellular carcinoma, the dose was considered to be minimized to avoid the side effects since the activity of drug-metabolizing enzymes may be decreased in hepatocellular carcinoma complicated with liver cirrhosis.

Efficacy of A-73209, a potent orally active agent against VZV and HSV infections.

A-73209 is a novel oxetanocin derivative with potent in vitro and in vivo activity against VZV, HSV-1, and HSV-2. A-73209 was two logs more potent than acyclovir against five thymidine kinase positive (TK+) strains of VZV in vitro (mean EC50 0.01 vs. 1.22 micrograms/ml). The activity of A-73209 was one log more potent than acyclovir against TK+ HSV-1 strains in vitro (EC50 = 0.03 vs. 0.32 micrograms/ml). A-73209 yielded a mean EC50 of 2.2 micrograms/ml compared to a mean EC50 of 0.37 micrograms/ml for acyclovir against a panel of TK+ HSV-2 strains in vitro. The in vitro activity of A-73209 against thymidine kinase negative or deficient strains of VZV, HSV-1 and HSV-2 was much lower than for the corresponding TK+ strains. A-73209 produced efficacy superior to acyclovir against lethal systemic or intracerebral HSV-1 infections in mice. The greater efficacy of A-73209 relative to acyclovir was especially apparent with oral dosing. Against HSV-2 infections in mice, the efficacy of A-73209 ranged from equal to 1.7 times less active relative to acyclovir with oral dosing. A-73209 was orally bioavailable in mice, with maximal serum concentrations well in excess of in vitro inhibitory concentrations. A-73209 appears to be a potent and selective agent against varicella-zoster virus and herpes simplex virus infections.

[Blood concentrations of futraful, uracil and 5-fluorouracil (5-FU) after UFT administration in the various reconstructions after gastrectomy. Saitama UFT Research Group].

The study was undertaken in the total of 58 gastric cancer patients among which 17 of Billroth (BI), 14 of Billroth II (B II) anastomosis after subtotal gastrectomy, and 7 of jejunal interposition, 9 of double tract and 11 of Roux en Y anastomosis after total gastrectomy were included. Blood samples were taken before 200 mg of per oral UFT administration and after 1, 2, 3, 5 and 7hrs. consecutively. The blood Futraful (FT) level in the total gastrectomy groups reached peak concentration within 1hr and kept in relatively high level during the observation period of 7hrs. The time to maximum FT concentration delayed in almost of B I and a few of B II patients. The concentration curves of uracil (URA) and 5-FU were similar in shape, revealing steep increase and decrease except B I anastomosis which showed gentle course. The plotted maximum concentrations of URA and 5-FU in the every type of reconstruction showed a significant correlation in the regression line. In the analysis of AUC, URA/FT was under 10%, suggesting the longer retention of the unmetabolite type of FT and early disappearance of URA. The ratio of 5-FU/FT was indifferent in each reconstruction. 5-FU/URA was higher in subtotal rather than total gastrectomy groups. From the data obtained, blood concentration of 5-FU after UFT administration was considered to depend on the emptying status in the gastrectomies. And moreover, it depended on blood URA level, since FT from which 5-FU was derived, was kept still sufficiently remained during observation period.

[A study of urinary tegafur, 5-fluorouracil (5-FU) and uracil concentrations in the cases of gastric carcinoma for the confirmation of drug-taking compliance after UFT oral administration].

We have measured urinary tegafur (FT), 5-FU and uracil concentrations after UFT oral administration (300 mg daily for 7 days) to confirm drug-taking compliance in the 17 cases undergone gastrectomy. Urinary FT and 5-FU concentrations reached to the plateau 2 and 3 days after administration, respectively, and were maintained until the day after termination of administration. Subsequently, FT and 5-FU concentrations also decreased about 50% at 2 day, 20% at 3 day, 10% of the plateau values at 4 day after termination, respectively. The mean plateau value of urinary FT was 12.9 +/- 6.8 micrograms/dl, and that of urinary 5-FU was 0.67 +/- 0.50 microgram/dl. On the other hand, uracil concentration, was not different before and after administration because of the uracil being present endogenously. Therefore, it was suggested that measurement of urinary FT and 5-FU concentrations is useful for confirmation of UFT-taking compliance.

[Multicenter cooperative study of pre- and post-operative adjuvant chemotherapy in the treatment of colorectal cancer. North Kyushu Co-operative Study Group for Cancer Chemotherapy].

The usefulness of pre- and post-operative adjuvant chemotherapy in colorectal cancer patients was studied by the North Kyushu Co-operative Study Group for Cancer Chemotherapy (21 participating institutions). Comparisons were made among group I given a tegafur suppository preoperatively+tegafur oral preparation postoperatively, group II given a tegafur suppository preoperatively+UFT oral preparation postoperatively and group III given a tegafur oral preparation postoperatively. No differences were seen in the incidence of postoperative complications depending on whether or not tegafur suppositories were administered preoperatively. There were also no differences in the symptom or incidence of side effects due to postoperative administration of tegafur or UFT. In a study of 5-FU concentration in the lymph nodes due to preoperative tegafur administration and recurrences, the concentration of 5-FU was significantly higher in the lymph nodes of cases without recurrences than in those with recurrences, and it was suggested that a relation exists between the concentration of agent and recurrences. The concentration of 5-FU in the lymph nodes of Dukes B patients was significantly higher in cases without recurrences than in those with recurrences. The non-recurrence rate (healthy rate) was better in the group given UFT postoperatively than in that administered tegafur postoperatively although the difference was not significant.

[Pre- and post-operative adjuvant chemotherapy of colorectal cancer. Part 1. Drug concentration in tissues following UFT administration].

The concentration of Tegafur, 5-FU and Uracil in tumor and normal tissue were measured in 47 colorectal cancer patients who had been administered UFT (400/mg) for seven days before operation. The concentration of Tegafur, 5-FU and Uracil in tumor was higher than in normal tissue (p less than 0.01), and the concentration of 5-FU was correlative to the concentration of Tegafur and Uracil in both tissues. The Dukes group and histological type were not related to the concentration of Tegafur, 5-FU and Uracil in either tissue. The uptake of each drug was good and high in tumor tissue.