The relationship between plasma pharmacokinetics and tissue metabolites of 5-fluorouracil (5-FU) in patients with colorectal cancer

To assess the relationship between the plasma pharmacokinetics of 5-Fluorouracil (5-FU) and the levels of intracellular 5-FU metabolites, we have studied eight patients presenting with primary carcinomas of the colon and rectum. Serum 5-FU levels and fluorinated metabolites within normal and malignant tissue were estimated using chromatographic methods. An analysis of the total fluorinated products against plasma halflife, plasma clearance and maximum plasma concentration failed to demonstrate any significant correlation. Furthermore the differing levels of 5-FU metabolites in normal and malignant tissue could not be correlated with the pharmacokinetic parameters studied. It is concluded that the cellular levels of active 5-FU metabolites reflect local cellular activity rather than the handling of the drug in vivo.     

Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile

Kinetics of 5-fluorouracil (FUra) and FUra metabolites in plasma and urine were investigated in 10 cancer patients following i.v. bolus administration of 500 mg/m2 FUra with 600 microCi of [6-3H]FUra. Biliary excretion was examined in two patients with external biliary catheters. Quantitation of unchanged drug and metabolites was assessed by a highly specific high-performance liquid chromatographic method. FUra plasma levels declined rapidly with an apparent elimination half-life of 12.9 +/- 7.3 min. Dihydrofluorouracil was detected within 5 min in most patients, demonstrating rapid catabolism and reached maximum peak levels of 23.7 +/- 9.9 microM at approximately 60 min. The apparent elimination half-life of dihydrofluorouracil (61.9 +/- 39.0 min) was consistently greater than that of the unchanged drug. The apparent elimination half-lives of the subsequent metabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine were prolonged with values of 238.9 +/- 175.4 min and 1976 +/- 358 min, respectively. Approximately 60-90% of the administered dose was excreted in urine within 24 h, primarily as alpha-fluoro-beta-alanine. Biliary excretion accounted for 2-3% of total administered radioactivity. The major fraction of this radioactivity eluted on high-performance liquid chromatography as a previously unrecognized FUra metabolite. Analysis of its structure is currently ongoing in our laboratory. In conclusion, this study provides the first comprehensive analysis of the formation and excretion of FUra metabolites in plasma, urine, and bile following i.v. bolus administration of FUra in humans.     

Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil

We have recently demonstrated that continuous-infusion (CI) 5-fluororacil (FU) eradicates human colon carcinoma cells made resistant to bolus FU in vitro. In addition, in the same experimental system, the mechanisms of resistance to pulse and CI FU were found to be different. These observations led us to test the clinical activity of a standard regimen of CI FU (300 mg/m² per day) in a cohort of 15 patients with advanced measurable colorectal cancer who were in progression after having failed to respond to bolus treatment with FU alone (3 patients) of FU combined with high-dose 6-S-leucovorin (LV) (12 patients). The median age of the patients was 68 years, and their median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. No myelotoxicity was observed. Mild diarrhea, mucositis, and vomiting occurred in 32%, 26%, and 19% of the patients, respectively, with no WHO grade 3 or 4 episodes being noted. In all, 6 of 15 patients complained of hand-foot syndrome, which was severe in 2 instances, lasting approximately 1 week. Overall, 1 partial response and 6 instances of disease stabilization, including 3 minor responses, were obtained both in patients who had been pretreated with pulse FU alone and in patients who had failed first-line treatment with FU+LV. Finally, 8 patients failed CI FU. In conclusion, these results, obtained in patients who were clearly progressing after having failed first-line treatment, support our experimental finding that resistance to bolus FU may be overcome by CI FU and extend this possibility to patients who are resistant to bolus treatment with FU+LV.This study was supported by CNR grants 92.01289. PF 70, 92.02271.PF39 and AIRC 1991. One of the authors (A. G.) is a fellow of the Associazione Italiana Ricerca Cancro     

Biochemical modulation of 5-fluorouracil: A randomized comparison of sequential methotrexate, 5-fluorouracil and leucovorin versus sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic colorectal cancer

BACKGROUND: The optimal chemotherapy for advanced colorectal carcinoma isnot known. Two regimens, both based upon biochemical modulationof 5-FU, were compared in a randomized multicenter trial. PATIENTS AND METHODS: A total of 202 symptomatic patients were randomly allocatedto receive either sequential methotrexate, 250 mg/m², duringthe first 2 hours and 5-FU, 500 mg/m², at hours 3 and 23 followedby leucovorin rescue initiated at hour 24 (15 mg x 8) (MFL)or sequential 5-FU 500 mg/m² followed by leucovorin 60 mg/m²30–40 minutes later, on days 1 and 2 (FLv). Treatmentswere repeated every 14 days for eight courses and then every3 to 4 weeks. Four patients were unevaluable. RESULTS: The two treatments were equally effective with respect to objectiveresponse rates (complete (CR) + partial (PR), MFL 17%, FLv 21%),subjective response rates (symptom relief in the absence ofsevere adverse effects, 45% vs. 37%), and survival (median 7.5vs. 9 months). All responses lasted at least 4 months. Overall,toxicity was low and comparable between the groups, but serioustoxicity was more common in the MFL group. CONCLUSIONS: Since FLv is easier to administer and carries less risk forserious toxicity, it should be recommended as a first-line treatmentbefore MFL. On either regimen, about 40% of symptomatic patientscan expect palliation, i.e., symptomatic relief without severeadverse effects, for at least 4 months. biochemical modulation, chemotherapy, colorectal cancer, 5-fluorouracil, subjective response     

Pharmacokinetics of levamisole in cancer patients treated with 5-fluorouracil

Purpose: To investigate the pharmacokinetics of levamisole and a metabolite, p-hydroxylevamisole in patients with colorectal cancer treated with 5-fluorouracil (5-FU). Methods: Following an intravenous bolus dose of 5-FU, 20 patients with colorectal cancer received oral doses of 50 mg levamisole every 8 h for 3 days. Immediately after the last dose, blood and urine samples were collected over at least an 8-h period. Samples were assayed for levamisole and p-hydroxylevamisole by GC/MS. The levamisole plasma and urine data were subjected to pharmacokinetic analysis using NONMEM software. Results: Substantial interpatient variability was observed in the levamisole plasma concentration-time curves. Patients with cardiovascular or gastrointestinal complications demonstrated altered absorption of levamisole. Pharmacokinetic parameter values for levamisole were similar to those obtained previously in healthy subjects and other cancer patients. Conclusions: There is no evidence that the pharmacokinetics of levamisole are altered by 5-FU administered immediately prior to levamisole administration. The relationship between the substantial intersubject variability in levamisole plasma concentration-time curves and clinical outcome following 5-FU/levamisole adjuvant chemotherapy should be examined. Received: 19 May 1999 / Accepted: 11 August 1999     

Pharmacokinetics of 5-fluorouracil in colorectal cancer patients receiving interferon

BACKGROUND:: The outlook for patients with advanced colorectal cancer remainspoor. Recent reports of the combination of 5-fluorouracil (5-FU)and -interferon in colorectal cancer have suggested better responserates. One possible explanation for interaction between 5-FUand interferon is that interferon alters the pharmacokineticsof 5-FU, increasing plasma 5-FU levels. PATIENTS AND METHODS:: To investigate the possibility of interaction between the twoagents, steady state 5-FU pharmacokinetics was evaluated inpatients with colorectal cancer who received 5-FU by continuousi.v. infusion with and without concurrent administration ofsubcutaneous -interferon. 5-FU levels were measured by reverse-phasehigh-performance liquid chromatography. RESULTS:: Twenty-six patients were evaluated. There were 4 partial responses(15%). There was no significant difference in steady state 5-FUlevels whether or not -interferon was administered concurrently. CONCLUSION:: Any synergistic activity that may exist between this combinationof 5-FU and -interferon is not simply due to altered 5-FU pharmacokinetics. colorectal cancer, 5-fluourouracil, -interferon, pharmacokinetics     

Cisplatin and 5-fluorouracil in refractory breast cancer patients: A phase II study

Summary 24 patients with a median of 3 prior chemotherapy regimens were treated in our department with cisplatin 20 mg/m² (with pre- and posthydration) and 5-fluorouracil 200 mg/m² i.v. on day 1–5, every three weeks. 23 patients are evaluable; one had early death. 4 patients (17%) achieved a partial response, 8 had stable disease, and 11 progressed. Toxicity observed was moderate and no renal toxicity was noted. This study therefore shows tolerable toxicity but limited usefulness of adding cisplatin to 5-fluorouracil according to this schedule in these highly pretreated patients.     

Plasma kinetics of aclacinomycin A and its major metabolites in man

Summary The plasma pharmacokinetics of the antineoplastic anthracycline antibiotic aclacinomycin A (Acm) and its metabolites were studied in 12 patients treated with 60–120 mg/m² during a phase I clinical trial. Total plasma drug fluorescence initially declined very rapidly, but from 2 to 24 h after injection, fluorescence rose progressively to intensities greater than those measured 1 min after Acm injection. Plasma total drug fluorescence slowly declined from 24 to 72 hours after Acm administration. These events reflected the rapid disappearance of Acm and the subsequent appearance of two highly fluorescent metabolites. One metabolite co-chromatographed with and had a fluorescence spectrum identical to known metabolite F₁ (bisanhydroaklavinone). The other metabolite did not co-chromatograph with any previously described Acm metabolite. This metabolite had a fluorescence spectrum unlike any previously described Acm metabolite and was not altered by treatment for 60 min with 0.2N HCl at 100°C or by treatment for 24h at 37°C with bacterial -glucuronidase or limpet aryl sulfatase.Abbreviations used Acm aclacinomycin A - Dnr daunorubicin - Ard adriamycin - TLC thin layer chromatography - MLAB on-line modeling laboratory, Division of Computer Resources and Technology, National Institutes of Health - CxT concentration times time - C_p plasma concentration - t Time after administration of drug - R_f relative retardation factor - HPLC high performance liquid chromatography     

Gemcitabine increases systemic 5-fluorouracil exposure in advanced cancer patients

A number of recent clinical trials testing the combination of 5-fluorouracil (5-FU) and gemcitabine in patients with advanced pancreatic adenocarcinoma have shown a significant clinical response rate, but also significant toxicity. As the two antimetabolites may interact at several biochemical levels along their pathways of activation, we investigated whether gemcitabine (GEM) affects 5-FU pharmacokinetics in cancer patients. Thus, we compared 5-FU pharmacokinetics in two groups of patients with various cancers who received the same schedule of 5-FU and folinic acid (FUFA), with or without GEM. There was a significant increase in systemic (5-FU) exposure and toxicity in the FUFA plus GEM group. Our finding may be useful in designing future studies of the combination in order to reduce the occurrence of side-effects and to maximise the antitumour activity.     

A comparative study of oral tegafur and intravenous 5-fluorouracil in patients with metastatic colorectal cancer

A randomized study was conducted in patients who had measurable metastatic colorectal cancer to compare the relative efficacy and toxicities of oral tegafur (1 gm/m2/days 1-21) with those of 5-fluorouracil (5-Fu, 500 mg/m2/days 1-4, then 250 mg/m2 on days 6, 8, 10, 12). The treatment courses were repeated every 4 weeks. Patients not responding to 5-Fu treatment were switched to tegafur. Randomization was stratified for presence or absence of liver metastasis and performance status. Partial responses were observed with 5-Fu, 6/32 (19%), tegafur, 7/35 (20%), and in patients who had been switched to tegafur after failing on 5-Fu, 1/20 (5%) with patients evaluable for response. Neutropenia was more common with 5-Fu (32% vs. 1% of treatment courses). Nausea occurred in about half the treatment courses; vomiting occurred in only 22%. Mucositis and diarrhea were more common with 5-Fu and severe in patients with liver function impairment. Neurologic toxicities due to tegafur were mild and occurred in less than 10% of the treatment courses. Oral tegafur and I.V. 5-Fu were equally effective against colorectal cancer, but tegafur was associated with minimal myelosuppression, which makes it suitable for use in combination with myelosuppressive antitumor agents.     

Sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic gastrointestinal cancer

50 patients with advanced symptomatic gastrointestinal cancer were treated with sequential 5-fluorouracil (5-FU)/leucovorin. Patients received an intravenous bolus injection of 5-FU (500 or 600 mg/m²) and leucovorin 30–40 min later, either 50 mg (41 patients) or 200 mg (9 patients). Treatment was given in repeated courses either once weekly or on 2 consecutive days every other week until progression. Toxicity was mild with the lower leucovorin dose, although grade 2 toxicity, particularly diarrhoea, occurred in 27 (66%) patients. All patients receiving the higher leucovorin dose had grade 2–4 toxicity. Toxicity was less with the lower 5-FU dose. Out of 40 patients with colorectal cancer, 34 received leucovorin 50 mg and 6 received 200 mg. Partial response occurred in 10 (29%) and 1 of these patients, respectively. This sequential 5-FU and intermediate-dose leucovorin regimen has acceptable toxicity and a definite anti-tumour activity.     

Risk factors associated with mucositis in cancer patients receiving 5-fluorouracil

Oral mucositis is a dose-limiting toxicity of 5-fluorouracil (5-FU). This prospective cohort study investigated factors associated with mucositis in patients receiving 5-FU for cancer of the digestive tract. Sixty-three patients (mean age 65 years) completed self-administered questionnaires and had interviews, oral examinations and unstimulated whole salivary flow measurements at baseline and follow-up appointments. The duration of follow-up was 2 months. Predictor variables included sociodemographic data, body surface area, diabetes, smoking, alcohol consumption, salivary flow, oral hygiene, presence of prostheses, performance status, regimen of cytotoxic drugs, hematological data, and herpes simplex virus antibody titer. Forty-six per cent of patients developed at least one episode of oral mucositis during cytotoxic treatment. Pearson's chi-square analysis showed that mucositis was significantly associated with xerostomia at baseline, xerostomia during chemotherapy, and lower baseline neutrophil counts (P≤0.05). Multiple logistic regression analysis indicated that xerostomia at baseline (odds ratio, OR=10.0), or baseline neutrophil level under 4000 cells/mm³ (OR=3.9) were significant predictors of mucositis. Taking into account the effect of neutrophil level at baseline, xerostomia during chemotherapy (OR=4.5) was also a significant predictor of mucositis. The results showed that xerostomia and lower baseline neutrophil levels are significantly associated with oral mucositis. These variables should be taken into consideration in the design of intervention studies to reduce the frequency and severity of mucositis. More research is required to investigate the role of saliva and neutrophils in the pathogenesis of chemotherapy-induced mucositis.     

The influence of 5-fluorouracil on cellular and humoral immunity in cancer patients

The effects of 5-fluorouracil (5-FU) on the immune functions of twelve patients with disseminated cancer were studied, using as parameters the peripheral blood lymphocyte count, serum immunoglobulin levels, titers of natural blood group antibodies, percentages of E and EAC rosette forming cells, and lymphocyte proliferative responses to PHA and PPD. No effects on the humoral immune functions or on the percentages of E and EAC rosette forming cells were observed. 5-FU caused a decrease in the proliferative responses of lymphocytes to PHA and PPD. The patients could be divided into two groups: those surviving for six months or more, and those succumbing earlier. The latter ones had already initially poor proliferative responses, particularly to PPD, and the response strongly decreased during the 5-FU treatment. In the patients with a longer survival time, the effects of 5-FU on the PPD and PHA responses were not as striking.     

Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients.

PURPOSE: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.     

Assay of intracellular free and macromolecular-bound metabolites of 5-fluorodeoxyuridine and 5-fluorouracil.

Methods have been developed to assay several aspects of 5-fluoro-2'-deoxyuridine and 5-fluorouracil metabolism in tissue culture cells. These methods allow measurement of (a) intracellular levels of the covalent complex formed between 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), 5,10-methylenetetrahydrofolate, and thymidylate synthetase; (b) incorporation of drug into RNA; and (c) analysis of drug metabolites. The methods were developed using radioactively labeled drugs, but they should be adaptable to studies using nonlabeled compounds. Sephadex G-25 chromatography or trichloroacetic acid precipitation were utilized for isolation of the macromolecular cell fraction; prior treatment of this fraction with RNase or heating at 65 degrees for 15 min resulted in selective removal of RNA or the thymidylate synthetase complex, respectively, from the precipitable fraction. Free intracellular drug metabolites present in the acid-soluble fraction were analyzed by high-pressure liquid chromatography. Following incubation of HTC cells with [6-3H]-5-fluoro-2'-deoxyuridine, a radioactive macromolecule was isolated and identified as a FdUMP-5,10-methylenetetrahydrofolate-thymidylate synthetase complex. Intracellular formation of this complex was shown to be dependent on the presence of the enzyme thymidine kinase. Dissociation of the complex in vivo was first order with a t1/2 of 6.2 hr; in contrast, a t1/2 of 2 hr was determined for dissociation of the complex in cytosol. Incubation of L1210 cells with [6-3H]-5-fluorouracil for 22 hr resulted in formation of 80 fmol of FdUMP-5,10-methylenetetrahydrofolate-thymidylate synthetase complex per 10(6) cells, as compared with 400 fmol of drug incorporated into RNA per 10(6) cells. Intracellular FdUMP could not be detected in the acid-soluble fraction of these cells unless the cells were first heated to dissociate the complex.     

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.     

A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients

BackgroundIn esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens.Patients and methodsThis multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m² and 1 g/m²) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m²).ResultsOverall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62–1.51]}, with a median survival of 16.1 (CI 11.8–20.5) and 13.8 months (CI 10.8–16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60–1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9–15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1–14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001).ConclusionsIn this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.     

A mathematical model for the age distribution of cancer in man

Incidence data that have been collected by cancer registries in different parts of the world provide an opportunity for examining the relationship between cancer incidence and age on a wider scale and more accurately than has been possible before. In the present paper the relationship has been examined in a large group of cancers whose incidence increases progressively from young adult life into old age. Five-year age-specific incidence rates between 35 and 74 years of age were recorded for 31 types of cancer (22 in men and 9 in women) in 11 populations, and the median age of each age group was used to characterize the group. The data were used to find the best fitting constants for each type of cancer in each population, in the equation: where I is the incidence at age t, and b and k are constants. With this equation a straight line is obtained, when incidence and age are plotted on a double logarithmic scale. On visual examination, 21% (72 out of 338) of the sets of data appeared to fit the relationship closely. In 54% (181 out of 338) the lines showed downward curvature; that is, the rate of increase with age was less than predicted by the equation; and in 25% (85 out of 338) the lines showed upward curvature. In one-third of the total the differences were too great to be readily attributable to chance. An alternative hypothesis was examined which postulated that the risk of cancer was determined, not by the age of the subject, but by the prevalence of carcinogenic agents and the length of time the subject had been exposed to them. The equation was then written: where w is a constant and t-w represents the ‘effective exposure’ between first exposure and the first appearance of cancer as a pathological entity. The data for cancer of the prostate were found to fit the equation adequately in all 11 populations, when w was 32.5 years. No evidence was found to suggest that the shape of the observed relationship could be attributed to attenuation of a limited pool of susceptibles. Changes in prevalence of carcinogenic agents could account for the variation in the pattern of the observed relationship, and the conditions under which this might occur are discussed. Differences in the estimated value of k (the power of the effective exposure time in the equation), were examined between (i) types of cancer and (ii) populations. The results were not wholly consistent but suggested that the value of k might be a biological constant characteristic of the tissue in which the cancer is produced.     

Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients

Summary Plasma concentrations of 5-fluorouracil (FU) and its primary catabolite, 5, 6-dihydro-5-fluorouracil (DHFU) were measured using gas-liquid chromatography after single-dose therapy with 7.2–14.4 mg/kg. Because of the limited sensitivity of the assay for drug levels in plasma, the urinary excretion of FU and metabolites was investigated using an ion-specific electrode after either a single bolus (7.0–9.6 mg/kg) or multiple-dose therapy (6.4–7.4 mg/kg/day). Half-life values for the elimination of FU from plasma (mean, 123.5 min) were greater in each patient than for the catabolite (mean, 109.2 min). Values of the area under the curve for FU profiles varied between patients (mean±SE, 12.7±1.9 g·h/ml) by comparison with the relatively constant values for curves of DHFU concentrations (mean±SE, 2.8±0.15 g·h/ml). In pharmacokinetic profiles of urinary excretion a transient phase of convex shape was apparent after 80%–98% of single doses of FU was excreted. Half-lives for the elimination of FU in urine were 2.6–5.9 h, which increased to 18–44 h on multiple dosing. The results demonstrate saturation in the elimination of FU after therapeutic doses, and are consistent with the proposal that reduction of FU to DHFU provides the rate-limiting step.