5FU Pharmacokinetics Research Articles

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic\u2013pharmacodynamic model in gastrointestinal cancer patients

PurposeTo describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach.MethodsThirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m2/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m2/day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics.ResultsTotal clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 109/L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg).ConclusionsBSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

Feasibility of 5-fluorouracil pharmacokinetic monitoring using the My-5FU PCM™ system in a quaternary oncology centre.

5-Fluorouracil (5FU) drug exposure correlates with treatment response and toxicity in cancer patients. Dosing is based upon body surface area which does not correlate with 5FU pharmacokinetics (PK)/pharmacodynamics. Therapeutic drug monitoring has enabled real-time 5FU dose adjustments: reducing toxicity with increased efficacy. The aim of this study was to assess feasibility of a 5FU monitoring service utilising a commercial kit in a quaternary cancer centre and to compare PK parameters to previously published studies. Cancer patients receiving continuous infusional (CI) 5FU with ECOG PS 0-2, and adequate organ function, were eligible. Patients had blood samples taken at t = 0, mid infusion (if feasible) then 2h pre infusion end. 5FU levels were measured using a commercial kit (My-5FU PCM™). A feasibility questionnaire was completed by trial nurses and toxicity data were recorded at baseline and at the commencement of the next cycle. 5FU pharmacokinetic exposure parameters were calculated. Twenty patients (12 male; 8 female), median age 62, (range 37-71) had samples taken. Twenty (100%) feasibility forms were available for assessment. Blood samples were taken at 51/69 (74%) specified time points. Ease of sample processing was recorded as easy in all 20 patients. Patient compliance with scheduled visits was 18/20 (90%). One form noted other difficulties with predicting end of infusion time. 19/20 patients had blood samples analysed. Mean measured 5FU AUC (0-Tlast) for 5FU 1g/m2 with platinum: 35.8h mg/L (range 28.56-44.26), mean Css 372.2µg/L (range 297.5-461.0); 5FU 600mg/m2 with platinum: 12.42h mg/L (range 6.91-18.29), mean Css 111.0µg/L (72.0-190.5) and 5FU 2400mg/m2 as part of FOLFOX ± bevacizumab: 14.75h mg/L (range 6.74-22.93), mean Css 320.70µg/L (range 146.5-498.5). One patient had grade 4 neutropenia and one patient without PK parameters experienced febrile neutropenia (grade 4 neutropenia). Mucositis was observed in two patients: [5FU/platinum (1), grade 1, FOXFOX ± bevacizumab (1) grade 1]. Diarrhoea was reported in three patients [5FU/platinum (2) grade 1-2, FOXFOX ± bevacizumab (1) grade 1]. Therapeutic 5FU drug monitoring was feasible using commercial kits and analysers and hence warrants development as a routine standard of care in cancer patients. The variability in the 5FU exposure parameters is consistent with other studies using the My 5FU PCM kit.

The impact of skeletal muscle on the pharmacokinetics and toxicity of 5-fluorouracil in colorectal cancer.

Great heterogeneity exists in the ability of adults with cancer to tolerate chemotherapy. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The objective of this exploratory study was to examine the association of low skeletal muscle, commonly known as sarcopenia, on the pharmacokinetics (PKs) of 5-fluorouracil (5FU) in patients receiving FOLFOX for colorectal cancer. We performed a secondary analysis of a completed multicenter trial that investigated PK-guided 5FU dosing in patients receiving mFOLFOX6 +/- bevacizumab for colorectal cancer. Cycle 1 PK samples were obtained 2-44h after the start of the 5FU infusion (steady state). No significant differences in first cycle 5FU area-under-the-concentration-time-curve (AUC) were found between sarcopenic and non-sarcopenic patients (17.3 vs. 19.3 AUC, p = 0.43). Patients with grade 3/4 toxicity had a higher dose of 5FU per kg lean body mass (LBM) (105 vs. 93mg/kg, p = 0.06), most notably for hematological toxicities (110 vs. 94mg/kg, p = 0.002); however, no correlation between the dose/LBM and 5FU AUC was found. Although our results did not confirm the impact of low skeletal muscle on PKs of 5FU, further research exploring the impact of body composition on chemotherapy PKs and related toxicities is warranted with the potential for alternative dosing strategies in sarcopenic patients to reduce unnecessary toxicities while maintaining efficacy.

Abstract 4205: Intracellular pharmacokinetics of 5FU and palbociclib: Uptake and efflux in disaggregated cells and 3D models

Abstract Introduction: Pre-clinical drug development does not routinely assess drug penetration beyond use of the human intestinal Caco-2 cell line as an in vitro model of the intestinal barrier to evaluate potential drug absorption. Detailed in vivo tumour pharmacokinetic (PK) studies are unusual. However, the ability of a drug to reach its target plays a key role in drug efficacy. Here we present a methodology to study drug PK in disaggregated cells and in a 3D cell culture model (spheroids) using 5FU and palbociclib. The comparison of these 2 drugs is of interest taking into account their different mechanisms and chemical properties, logP 0.58 and 2.12 respectively. Knowledge of cellular uptake and efflux in disaggregated cells and 3D models together with intracellular binding characteristics is vital to optimise a better drug delivery. Experimental procedures: MCF-7 and DLD-1 cells were used for cellular and spheroid experiments. Spheroid growth was optimized to produce a spheroid of 300-400µm diameter at day 4. Drug uptake: 1x106 cells or 30 spheroids/time point were exposed to 10µM 5FU or 0.1µM of palbociclib for different time durations. For 5FU, drug uptake at 100µM was also monitored to detect 5FU metabolites. Drug efflux: 1x106 cells were exposed first to 100µM 5FU or 0.1µM of palbociclib for 60min then, drug media removed, substituted by fresh media and sample over a 4h period. Drug concentration inside cells and in the fresh media was measured. Drug concentrations were measured using HPLC-Tandem Mass Spectrometry. Each experiment was carried out in triplicate. Results: 5FU achieves intracellular steady state within 5-10min in cells and spheroids with equal concentrations inside and outside the cell/spheroids. Intracellular metabolites of 5FU were only seen with 100µM treatment and had a similar PK characteristics to 5FU. 5FU drug efflux experiments showed that efflux occurred rapidly within 5min achieving a new equilibrium with 30% of 5FU remaining inside the cells. 5FUrd was also detected extracellularly after 1h in the fresh media, showing that cells have both 5FU and metabolite efflux. In contrast, palbociclib cellular uptake had an initial intracellular drug concentration peak at 5-10min which then plateaued. Interestingly, total intracellular concentrations of palbociclib were over 30 times higher compared to the external media drug at steady state. Spheroid and efflux experiments of palbociclib are on-going and will be presented. Conclusions: Our results suggest that both drugs penetrate quickly in cancer cells. Palbociclib intracellular concentrations were 30 times higher than the external media suggesting excessive intracellular binding while 5FU achieve equal concentrations between the inside and outside of the cell. These data and methodology may be useful to allow generation of mathematical models to improve drug delivery design. Citation Format: Maria Jove, Paul Loadman, Jade Spencer, Lava Sulayman, Jo Wicks, Amanda Race, Chris Twelves. Intracellular pharmacokinetics of 5FU and palbociclib: Uptake and efflux in disaggregated cells and 3D models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4205. doi:10.1158/1538-7445.AM2017-4205

Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a C.1905+1G>A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency. Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data. In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V(max)) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with V(max) values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for V(max), calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n = 10). Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.

Can localised 19F magnetic resonance spectroscopy pharmacokinetics of 5FU in colorectal metastases predict clinical response?

Background5-Fluorouracil remains widely used in colorectal cancer treatment more than 40 years after its development. 19F magnetic resonance spectroscopy can be used in vivo to measure 5FU’s half-life and metabolism to cytotoxic fluoronucleotides. Previous studies have shown better survival associated with longer 5FU tumour half-life. This work investigated 5FU pharmacokinetics in liver metastases of colorectal cancer.MethodsA total of 32 subjects with colorectal cancer undergoing 5FU treatment, 15 of whom had liver metastases, were examined in a 1.5T MRI scanner, using a large coil positioned over the liver. Non-localised spectra were acquired in 1-min blocks for 32 min after injection of a 5FU bolus. The 5FU half-life was measured in each subject, and averaged spectra were examined for the presence of fluoronucleotides. Associations with progression-free survival were assessed.ResultsNo association was observed between 5FU half-life, tumour burden and survival. Half-lives were all shorter than those associated with improved survival in the literature. Remarkably, in the group with liver metastases, high levels of fluoronucleotides were associated with poorer survival; this counterintuitive result may be due to the higher levels of fluoronucleotides (whose level is higher in tumour tissue than in normal liver) in patients with higher tumour burdens.ConclusionsIt is recommended that future studies use chemical shift imaging at higher field strengths to better resolve tumour from normal liver. Non-localised spectroscopy retains prognostic potential by enabling straightforward detection of fluoronucleotides, which are present at very low concentrations distributed throughout the tissue.

Abstract 2621: Telomere length in peripheral blood mononuclear cells (PBMNC) predicts for leukopenia, neutropenia and mucositis in colorectal cancer patients treated with 5FU

Abstract Defining the parameters contributing to variability in clinical toxicity is necessary to optimise cancer treatment. Some variability is accounted for by variations in 5FU pharmacokinetics, differences in co-morbidity (liver &amp; renal), pre-disposing factors (gender &amp; age). But a considerable amount remains unexplained. This study aims to identify various factors contributing to such toxicity in colorectal cancer patients receiving 5FU. The variables chosen for study include those that control 5FU metabolism including measures of dihydropyrimidine dehydrogenase (DPD) activity which is critical for 5FU catabolism, together with polymorphic analysis of thymidylate synthase (TS), methyltetrahydrofolate reductase (MTHFR) and methionine synthase (MS) activity. The addition of pharmacodymamics and the ability of end-organs to respond to drug treatment further refined the predictive model, particularly the ability to identify those patients most likely to experience severe myelosuppression in response to chemotherapy. In this regard, the replicative capacity of bone marrow progenitors was determined by measuring telomere length (TL) in peripheral blood mononuclear cells (PBMNC). Clinical toxicity was determined in 42 colorectal patients receiving 5FU. Toxicity (≥ grade 2) included neutropenia (n=25), leukopenia (n=14), mucositis (n=19) and diarrhea (n=5). While the severity of toxicity significantly correlated with the magnitude of the insult, ie 5FU dose, the analysis also showed that toxicity significantly correlated with TL, with short telomeres predicting for higher toxicity. Univariate analysis showed TL significantly correlated with leukopenia (r=-0.461, P=0.009), neutropenia (r=-0.413, P=0.021) and mucositis (r=-0.341, P=0.048). Multivariate analysis further confirmed the significant role of TL in these clinical toxicities. Collectively, these results support the link between TL and progenitor replicative capacity. In conclusion, PBMNC TL may be exploited to tailor chemotherapy schedules for colorectal cancer patients receiving 5FU. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2621.

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

5-fluorouracil (5FU) pharmacokinetic and hormonal status in female colorectal cancer patients

13576 Background: It is well known that females present a significantly reduced clearance of 5FU compared to males treated with the same doses.We tested the hypothesis that it may depend on the hormonal status, so that pre-menopausal women would have different 5FU pharmacokinetics compared with both postmenopausal women and elderly women. Methods: 48 colorectal cancer patients were prospectively studied: all of them were on adjuvant treatment based on 5FU repeated boluses. On the second day of the first cycle peripheral blood was drawn after drug administration. Plasma level were detected by HPLC analysis and pharmacokinetic parameters were calculated trough a one phase exponential decay model. Results: All patients had 100–90 Karnosky Performance status score. 12 were in pre-menopausal phase (age range : 40–55 years); among the others we distinguished a younger 19 people group (age lower than 70 years old) and an elderly 17 patient group (age equal or higher than 70 years old). They received a 5FU mean dose of 406 ± 15 mg/mq, not significantly different among the three groups. After intravenous bolus injection a high interindividual variability of 5-FU pharmacokinetics was detected: AUC0-∞ (area under the curve of drug plasma levels versus time) ranged between 368 and 1236 mg × min/L and the highest values (&gt;1000) were found in two elderly patients, considered fit; anyway there was no significant difference among AUC of the three groups. 5FU total clearance ranged between 0.53 and 1.9 L/min and means were 1.07 ± 0.3, 1.02 ± 0.3 and 0.98 ± 0.3 L/min in pre-menopausal, postmenopausal and elderly women respectively; again 5FU clearance/ BSA (body surface area), half live elimination times and peak concentration plasma levels were not significantly different among the three groups. Conclusions: It seems that sexual hormonal status do not influence 5FU total body elimination capability, and that pharmacokinetic differences between genders should be related to other factors,as for example Body Composition. Funded by AIRC-Veneto No significant financial relationships to disclose.

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours

We have shown previously that carbogen (95% 0(2), 5% CO(2)) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy ((19)F-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using (31)P-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. In both tumour models, carbogan-induced GRE-MRI signal intensity increases of approximately 60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, (19)F-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and (31)P-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, (19)F-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly ( p=0.0003) increased 5FU elimination from the tumour (i.e. decreased the t(1/2)) and significantly ( p=0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. (31)P-MRS showed there were significant ( p<or=0.02) increases in the hepatoma NTP/Pi ratio of 49% and transmembrane pH gradient of 0.11 units. We suggest that carbogen can transiently increase tumour blood flow, but this effect alone may not increase uptake of anticancer drugs without a secondary mechanism operating. In the case of the hepatoma, the increase in tumour energy status and pH gradient may be sufficient to augment 5FU metabolism to cytotoxic FNuct, while in the GH3 xenografts this was not the case. Thus carbogen breathing does not universally lead to increased uptake of anticancer drugs.

Human tumor fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics.

We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast, colon, endometrium, cervix, and kidney, using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems, Cerrito, CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis, breast, lung, and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes), much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides, nucleotides, 5FU-RNA, or 5FU-thymidylate synthase) nor the catabolites (eg, fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU, or 5FU or FUdR plus leucovorin, four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy, whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible, and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.

Fluorouracil: biochemistry and pharmacology.

Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.