Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg/m2/day for 5 days. After a washout period of 9 days, the 10 patients received two divided doses daily for 28 days. S-1 was administered orally at about 9 a.m. and 7 p.m. Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition in the same 10 patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC0-10h) of 5-FU on day 5 was 728 +/- 113 ng x hr/ml for PVI of 5-FU and 1,364 +/- 374 ng x hr/ml for S-1. The median 5-FU PVI: S-1 ratio of the AUC0-10h of 5-FU was 1.9. The AUC0-10h of FBAL on day 5 of PVI of 5-FU was 9,465 +/- 3,225 ng x hr/ml, AUC0-10h, as compared with 1,725 +/- 605 ng x hr/ml on day 5 of S-1 treatment. The AUC0-10h of uracil on day 5 was 252 +/- 60 ng x hr/ml with PVI of 5-FU and 12,582 +/- 3,060 ng x hr/ml with S-1. The AUC0-10h of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.     

Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug.

S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.     

Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy

We studied whether total gastrectomy for gastric cancer would affect the pharmacokinetics of 5-fluorouracil (5-FU) and its degradation products, such as dihydrouracil (FUH(2)) and alpha-fluoro-beta-alanine (FBAL), after oral administration of the fluorouracil derivative S-1, composed of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP; a dihydropyrimidine dehydrogenase inhibitor) and potassium oxonate. Blood and urine samples were obtained, both preoperatively and at least 2 weeks postoperatively, from six patients with advanced gastric cancers who were undergoing total gastrectomy. Plasma levels of tegafur, 5-FU, CDHP, potassium oxonate, FUH(2) and FBAL were measured prior to and at 1, 2, 4, 6 and 10 h after oral administration of 40 mg/m(2) S-1. The total amounts of 5-FU, FUH(2) and FBAL excreted into urine during the 24-h period after S-1 administration were also measured. Total gastrectomy significantly increased the maximum concentration and the area under the curve until 10 h after administration (AUC(1-10h)) of plasma 5-FU. The plasma AUC(1-10h) of CDHP was significantly higher than the preoperative value. In terms of clinical efficacy, the higher AUC(1-10h) of 5-FU after total gastrectomy may be beneficial to S-1 administered as adjuvant chemotherapy, and might be caused by the higher postoperative AUC(1-10h) of CDHP relative to preoperative values. However, the dose of S-1 for patients who have undergone total gastrectomy might be diminished to avoid severe adverse events and to continue the treatment for a long period.     

Plasma level of a 5-fluorouracil metabolite, fluoro-beta-alanine correlates with dihydropyrimidine dehydrogenase activity of peripheral blood mononuclear cells in 5-fluorouracil treated patients

5-fluorouracil (5-FU) is mostly metabolized after administration, and the metabolizing enzyme, dihydropyrimidine dehydrogenase (DPD), seems to be the rate-limiting factor. However, there are few reports on the final metabolite, fluoro-beta-alanine (FBAL). We report here the results of determination of the FBAL level in 5-FU treated patients and the correlation between the FBAL level and the DPD activity in peripheral blood mononuclear cells (PBMCs). Blood samples were collected from 20 patients, who had received continuous intravenous infusion (CIV) of 5-FU (320 mg/m2/24 hr) after resection of colorectal cancer, and the FBAL level was determined by high performance liquid chromatography (HPLC), after derivatizing into o-phthalaldehyde (OPA) and detecting fluorescence. DPD activity was measured in cytosol prepared from PBMCs using HPLC radioassay. The average FBAL plasma level during CIV of 5-FU was 911.0 ng/ml (521.0 to approximately 1834.6 ng/ml) and that of DPD activity in PBMCs was 282.6 pmol/min/mg-protein (145.0 to approximately 568.0 pmol/min/mg-protein). There was a significant correlation between the FBAL level and the DPD activity (r=0.805, p<0.0001). FBAL level in plasma may be useful in predicting the DPD activity in PBMCs, however, further studies are required considering the small number of cases in this study.     

Pharmacokinetics of S-1, an oral formulation of ftorafur,oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors

S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m(2). The plasma C(max) values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1-2 h were in the ranges 5.8-13 microM, 0.4-2.4 microM, 0.026-1.337 microM, and 1.1-3.6 microM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03-0.25 microM to 3.6-9.4 microM after 2-4 h, and 0.09-0.9 microM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418-1735 and 2281-8627 micromol x min/l, respectively. The t(1/2) values were in the ranges 213-692 and 216-354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2-11.9%; the urinary excretion of both fluoro-beta-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 microM and uracil was in the micromolar range (up to 7 microM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition.     

Pharmacokinetics of 5-FU after S-1 oral administration for adjuvant chemotherapy in gastric cancer patients

We studied the pharmacokinetics of 5-FU after S-1 oral administration at the usual dose (80 mg/m2) for adjuvant chemotherapy in 13 advanced gastric cancer patients (Stage II, III), and at a decreased dose (60 mg/m2) for adjuvant or combined chemotherapy in 13 advanced gastric cancer patients. Pharmacokinetic parameters of 5-FU in the serum were as follows: Cmax, 159 .9 2+/-45.2 ng/mL, Tmax, 2.17+/-0.58 h;T1/2, 3.13+/-2.88 h; and AUC(0-8), 768.0+/-260.8 ng h/mL in the patients with the usual dose, and Cmax, 117.3+/-55.1 ng/mL; Tmax, 2.62+/-0.9 6 h; T1/2, 3.09+/-1.9 5 h and AUC(0-8), 565.9+/-216.8 ng h/mL in the patients with the decreased dose. No difference in AUC was observed between operative methods. Adverse events of more than grade 3 were recognized in 7 patients, and AUC of 6 patients were more than 800 ng h/mL. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3-4 times. It was concluded that we must pay attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when S-1 would be administered.     

5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine

Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity.     

Dihydropyrimidine dehydrogenase activity in lymphocytes: predictive factor for 5-fluorouracil clearance]

We previously have shown that pharmacokinetic monitoring of 5-fluorouracil (5-FU) could significantly improve the 5-FU therapeutic index when given in continuous venous infusion (Br J Cancer 59, 287-290, 1989). However, the more rational approach would be to find individual biological factors which could predict 5-FU clearance. Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-FU. DPD activity was measured in 57 head and neck cancer patients receiving CDDP (100 mg/m2, day 1) plus 5-FU (1 g/m2/day x 5, day 2-day 6). DPD activity was measured in lymphocytes using a radioenzymatic assay (2.5 mM MgCl2, 250 microM NADPH, 20 microM 14C-5-FU) with separation of 14C-5-FU from 14C-5-FUH2 by HPLC coupled with a radiodetector. The average DPD activity measured in lymphocytes was 0.186 +/- 0.068 nmol/min/mg protein (range 0.058-0.357) and the average 5-FU clearance (Cl) was 2,523 +/- 684 ml/min/m2 (range 1,052-4,029). A significant linear correlation was demonstrated between DPD activity and 5-FU clearance (Cl = 1,099 + 7,580 DPD, r2 = 0.613, P < 0.0001). In patients evaluated for more than one cycle (n = 18), variations in 5-FU clearance were associated with corresponding variations in DPD activity. The individual determination of DPD activity measured in lymphocytes could be useful for identifying patients at risk for altered 5-FU pharmacokinetics and could be used to adjust the optimal 5-FU dose for each patient before starting the treatment.     

Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for > or = 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C(P)) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng x h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng x h/mL, respectively [P <.00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C(P) and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.     

Comparative pharmacokinetic analysis of 5-fluorouracil and its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer patients.

The aim of this study was to investigate the clinical pharmacokinetics of 5-fluorouracil (5-FU) and its major metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in 20 colorectal cancer patients given two dose levels of 5-FU, 250 and 370 mg/m2, administered by i.v. bolus. A reverse-phase high-performance liquid chromatographic method was used for the simultaneous assay of 5-FU and 5-FDHU in plasma samples obtained at baseline and at multiple time points from 5 min to 4 h after 5-FU bolus as well as to assess the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells (PBMCs) before 5-FU dosing. Plasma pharmacokinetic parameters of patients given 250 mg/m2 5-FU were significantly different from those receiving 370 mg/m2; main differences were observed in the trapezoidal areas under the plasma levels-versus-time curve from to to the last measurable concentration (area under the curve, 3.77+/-0.21 versus 13.61+/-2.3 h x microg/ml), peak plasma concentration (Cmax, 18.15+/-1.35 versus 48.41+/-7.69 microg/ml), and total body clearance (CL(TB), 54.64+/-3.54 versus 25.43+/-2.3 l/h/m2). Significant differences were also observed in the main pharmacokinetic parameters of 5-FDHU after 250 and 370 mg/m2 5-FU including the area under the curve from to to 4 h (5.39+/-0.32 versus 8.75+/-1.24 h x microg/ml), Cmax (3.60+/-0.16 versus 5.26+/-0.55 microg/ml) and time to Cmax (Tmax, 0.45+/-0.03 versus 0.69+/-0.06 h). The mean DPD activity in PBMCs in this group of patients was 205.7+/-36.4 pmol of 5-FDHU/min/mg of protein and was within the normal range; however, no significant correlations were found between 5-FU or 5-FDHU pharmacokinetic parameters at two dose levels and DPD activity of PBMCs. The results of the present study provide the first detailed comparison of the distribution of 5-FU and its major metabolite 5-FDHU at the therapeutic level as well as at reduced test dose levels to obtain pharmacokinetic data to be used as reference values for the identification of patients at risk of major 5-FU toxicity due to impaired metabolism to 5-FDHU.     

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Purpose The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated. Patients and methods A dose of 40 mg/m² of S-1 was administered orally twice daily for 7 days (80 mg/m²/day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre- and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined. Results At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 ± 304 ng h/ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 ± 331, 1,070 ± 403, and 946 ± 226 ng h/ml, respectively. No significant differences for plasma 5-FU were observed between pre- and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 ± 83 ng/g around 4.5 h and 91.7 ± 37.0 ng/g around 20 h after the final administration, respectively. Conclusion Gastrectomy does not affect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer.     

Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients.

Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in the catabolism of 5-fluorouracil (5-FU). We measured DPD activity in lymphocytes from 57 consecutive head and neck cancer patients while simultaneously monitoring 5-FU pharmacokinetics during 5-day, continuous infusion (1000 mg/m2/day) 5-FU therapy (82 cycles in total). The mean value for DPD activity was 0.186 +/- 0.068 (SD) nmol/min/mg of protein (range, 0.058 to 0.357). The mean value for 5-FU clearance was 2522.6 +/- 684.2 ml/min/m2 (range, 1052 to 4029). A significant linear correlation was observed between DPD activity and 5-FU clearance (r = 0.716, P less than 0.0001). DPD activity was poorly correlated to plasma uracil concentrations (r = -0.260, P = 0.0215). Likewise, plasma uracil concentrations were poorly correlated to 5-FU clearance (r = -0.214, P = 0.0595). In patients evaluated for more than one cycle (n = 18), there was large intrapatient variability in both DPD activity and 5-FU clearance. No significant difference was noted between cycles for DPD activity or 5-FU clearance (Kruskal-Wallis test). Monitoring DPD activity in lymphocytes may be useful in identifying patients at risk for altered 5-FU disposition.     

Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells

We analyzed dihydropyrimidine dehydrogenase (DPD) activity (radioenzymatic assay) and 5-fluorouracil (5-FU) cytotoxicity (MTT test) in the absence or presence of uracil in two human cancer cell lines, MIAPaCa-2 (pancreas tumor) and HuTu80 (duodenum tumor). Basal DPD activities in both were comparatively high; MIAPaCa-2, 101 and HuTu80, 153 pmol/min/mg protein, respectively. Twenty mu g/ml of uracil, a dose which did not influence cell proliferation, enhanced 5-FU cytotoxicity; MIAPaCa-2, 2.0-fold and HuTu80, 1.5-fold, respectively. Uracil inhibited both DPD activity and cell growth in a concentration-dependent manner, and exhibited maximum effect at molar ratios to 5-FU of more than 10 (DPD activity, almost complete inhibition; growth-inhibitory effect, about a 30% increase). In addition, the cytosolic DPD activity of OCC-1 human head and neck tumors, collected following the oral administration of ss mg/kg of uracil to tumor-bearing nude mice, decreased to about 50% of that of OCC-1 tumors not treated with uracil. These findings suggested that combined fluoropyrimidine and uracil treatment of tumors with high basal DPD, elicits a greater antitumor effect than fluoropyrimidines alone, since uracil could inhibit the degradation of 5-FU in the tumor. UFT, an oral fluoropyrimidine combined with uracil, is expected to be more effective in such tumors.     

Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies

Background:This study was performed to evaluate thepharmacokinetics, bioequivalence, and feasibility of a combined oralformulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc.,Research Triangle Park, North Carolina), an inactivator of dihydropyrimidinedehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FUformulation oral dosing form is to simplify treatment with these agents, whichhas been performed using separate dosing forms, and decrease the probabilityof severe toxicity and/or suboptimal therapeutic results caused byinadvertently high or conversely insufficient 5-FU dosing. Patients and methods:The trial was a randomized, three-waycrossover bioequivalence study of three oral dosing forms of eniluracil/5-FUtablets in adults with solid malignancies. Each period consisted of two daysof treatment and a five- to seven-day washout phase. Eniluracil at a dose of20 mg, which results in maximal DPD inactivation, was administered twice dailyon the first day and in the evening on the second day of each of the threetreatments. On the morning of the second day, all patients received a totaleniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as eitherseparate tablets (treatment A) or combined eniluracil/5-FU tablets in twodifferent strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). Thepharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinaryexcretion of eniluracil, 5-FU, uracil, and -fluoro--alanine (FBAL),were studied. To determine the bioequivalence of the combined eniluracil/5-FUdosing forms compared to the separate tablets, an analysis of variance onpharmacokinetic parameters reflecting eniluracil and 5-FU exposure wasperformed. Results:Thirty-nine patients with advanced solid malignancies hadcomplete pharmacokinetic studies performed during treatments A, B, and C. Thepharmacokinetics of eniluracil and 5-FU were similar among the three types oftreatment. Both strengths of the combined eniluracil/5-FU dosing form and theseparate dosing forms were bioequivalent. Mean values for terminal half-life,systemic clearance, and apparent volume of distribution for oral 5-FU duringtreatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variationfor pharmacokinetic variables reflecting 5-FU exposure and clearance intreatments ranged from 23% to 33%. The urinary excretion ofunchanged 5-FU over 24 hours following treatments A, B, and C averaged52.2%, 56.1%, and 50.8% of the administered dose of 5-FU,respectively. Parameters reflecting DPD inhibition, including plasma uraciland urinary FBAL excretion following treatments A, B, and C were similar.Toxicity was generally mild and similar following all three types oftreatments. Conclusions:The pharmacokinetics of 5-FU and eniluracil weresimilar and met bioequivalence criteria following treatment with the separateoral formulations of 5-FU and eniluracil and two strengths of the combinedformulation. The availability of a combined eniluracil/5-FU oral dosing formwill likely simplify dosing and decrease the probability of severe toxicityor suboptimal therapeutic results caused by an inadvertent 5-FU overdose orinsufficient 5-FU dosing in the case of separate oral formulations, therebyenhancing the overall feasibility and therapeutic index of oral 5-FU therapy.     

Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background:Previous work demonstrated that 5-fluorouracil(5-FU) metabolism is a critical factor for treatment tolerability. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability. Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria. Results:DPD activity in patients with mild toxicities (WHOgrade 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein,while in five patients with grade 3–4 gastrointestinal toxicity,DPD ranged from low to normal values (range 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe curve (AUC) was higher (range 14.70–26.20 h×µg/ml)than those observed in 84 patients with mild toxicities (CL, 56.30± 3.60 l/h/m²; AUC, 7.91 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity. Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.     

Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrent or advanced head and neck cancer.

5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged drug exposure, 5-FU is commonly given by continuous infusion. Eniluracil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule. Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7). 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum 5-FU and uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2 5-FU BID. One patient died of neutropenic sepsis during cycle 4. Other late cycle toxicities included diarrhea, fatigue, and mucositis. Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral 5-FU given with the DPD-inactivator eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting mucositis and dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of eniluracil and 5-FU as radiation enhancers.     

Protracted venous infusion 5-fluorouracil with concomitant radiotherapy compared with bolus 5-fluorouracil for unresectable pancreatic cancer

Radiation therapy (RT) with concurrent 5-fluorouracil (5-FU) administered by protracted venous infusion (PVI) replaced our prior institutional protocol of RT with bolus administration of 5-FU as standard therapy for unresectable pancreatic cancer in 1994. In this article, we compare the treatment intensity, toxicity, and outcome for patients with unresectable pancreatic cancer treated on these sequential protocols. Fifty-four patients, 27 on each protocol, with biopsy-confirmed pancreatic cancer received chemoradiotherapy. The radiotherapy field included the gross tumor volume and regional lymph nodes to a dose of 45 Gy, followed by "boost" to the gross tumor volume to 54 Gy to 60 Gy. From 1987 to 1994, patients received concurrent 5-FU administered by bolus injection, at a dose of 500 mg/m2 on days 1 to 3 and days 29 to 31 of RT. After December 1994, 5-FU was administered by PVI (200-250 mg/m2) beginning on day 1 and continuing until the completion of RT. The chemotherapy treatment intensity was increased in the group receiving 5-FU by PVI, as evidenced by an increased average weekly and cumulative dose of 5-FU (p < 0.01). The radiotherapy treatment intensity was equivalent between the two groups. The incidence of objectively quantified toxicity was not statistically different between treatment groups. Overall survival remained poor in both treatment groups. With a median follow-up of 18 months (range: 3-30 months) for surviving patients, the 6-month, 1-year, and 2-year survivals for the PVI 5-FU-treated group versus the bolus 5-FU-treated group were 56% versus 52%, 34% versus 18%, and 22% versus 13%, respectively (p = 0.9). Radiotherapy with concomitant 5-FU by PVI results in a greater weekly and total dose of chemotherapy. The method of 5-FU administration (bolus versus PVI) did not change the RT treatment intensity, experienced toxicity, or overall survival.     

Phase I and pharmacokinetic study of once daily oral administration of S-1 in patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities(DLTs), and pharmacokinetics of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oxonic acid, administered once daily in patients with advanced cancer. EXPERIMENTAL DESIGN: Eighteen patients with refractory malignancies were treated with S-1 administered once daily for 21 consecutive days, followed by a 1-week break. Of 16 evaluable patients, 6 were treated at a dose of 50 mg/m(2)/day, and 10 were treated at 60 mg/m(2)/day. RESULTS: DLTs were observed in 1 of 6 evaluable patients treated with 50 mg/m(2)/day and in 4 of 10 evaluable patients treated with 60 mg/m(2)/day. DLTs included diarrhea, nausea/vomiting, fatigue, and hyperbilirubinemia. The maximum tolerated dose was 50 mg/m(2)/day. Pharmacokinetic data are consistent with potent modulation of 5-fluorouracil (5-FU) by CDHP, with prolonged half-life and 5-FU AUC at least 10-fold higher than reported in previous studies of equitoxic doses of tegafur modulated by uracil. Pharmacodynamic analysis demonstrated a correlation between diarrhea grade and both 5-FU C(max) (r = 0.57, P < 0.05) and 5-FU area under the curve (r = 0.74, P < 0.01). CONCLUSIONS: The recommended Phase II dose of S-1 administered once daily for 21 consecutive days of 28 is 50 mg/m(2). The pharmacokinetic data presented provide evidence of 5-FU modulation by CDHP. Pharmacodynamic analyses suggest that the utility of pharmacology-based dosing of S-1 should be explored in future trials. Evaluation of once-daily dosing of S-1 in malignancies for which fluoropyrimidines have known antitumor activity is warranted.     

5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer.

PURPOSE: To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU-based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study. EXPERIMENTAL DESIGN: One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of l-leucovorin 100 mg/m(2)/day and 5-FU 370 mg/m(2)/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS. RESULTS: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 +/- 2.9 h x mg/L) with respect to other patients (9.3 +/- 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06). CONCLUSIONS: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.     

Effects of the plasma concentration of 5-fluorouracil and the duration of continuous venous infusion of 5-fluorouracil with an inhibitor of 5-fluorouracil degradation on Yoshida sarcomas in rats

The correlations of the 5-fluorouracil (5-FU) level in the plasma and the duration of continuous 5-FU infusion with the antitumor activity of 5-FU on Yoshida sarcomas in rats were examined. The circadian variation in the plasma level of 5-FU during continuous infusion was prevented by treatment with 3-cyano-2,6-dihydroxypyridine (CNDP), which strongly inhibits 5-FU degradation. On continuous venous infusion of 2 to 30 mg/kg of 5-FU over 24 h with CNDP at a molar ratio of 1:10 into normal rats, the 5-FU level in the blood was linearly proportional to the dose of 5-FU. The optimum schedule for antitumor activity on Yoshida sarcomas in rats was found to be infusion of 5-FU at 5 mg/kg over 24 h for 6 consecutive days, which gave a plasma 5-FU level of 176 ng/ml. Continuous infusion of 5-FU to give a plasma level of 300 ng/ml for 6 consecutive days from day 5 after implantation of tumor cells, when the tumors weighed about 1.0 g, resulted in complete regression of the tumors in all rats.