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DRUG METABOLISM |
From the Clinical Pharmacology Research Center, Peking Union Medical University Hospital, Beijing, China (Dr H Jiang, Dr J Jiang, Dr Hu) and the Department of Anatomy and Cell Biology, Temple University, Philadelphia, Pennsylvania (Dr Lu).
Address for reprints: Hao Jiang, Department of Pharmacology, University of Pennsylvania School of Medicine, 135 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Dihydrouracil/uracil ratio • gestational trophoblastic tumor • 5-fluorouracil • floxuridine • individual dose adjustment
85% of 5-FU administered and, therefore, directly influenced 5-FU entering into its corresponding anabolic pathways to exert its cytotoxic effects. Although complete DPD deficiency in the large population was only 3%, partial deficiency and overexpression of DPD in patients were frequently found.12-14 Such variations in DPD levels caused difficulty in setting a clinical administration dose prior to 5-FU chemotherapy. Thus, the polymorphism of DPD in patients has been regarded as a potential index in predicting the 5-FU dose for patients with obvious deficiency/overexpression in DPD rather than body weight (BW) or body surface.15,16 Until now, many researchers have attempted to find a predictor that could directly reflect the polymorphism of DPD in clinical patients. Fleming et al17,18 first found a significant correlation between peripheral blood mononuclear cell-DPD (PBMC-DPD) and 5-FU plasma systemic clearance, which indicated that the PBMC-DPD might be a potential predictor for the systematic DPD level. Bi et al19 and Morimoto et al20 hypothesized and proved that the concentrations of uracil and its dihydrogenated metabolite (dihydrouracil) catabolized by DPD were the potential predictors for 5-FU catabolism in vivo. Furthermore, Gamelin et al16 investigated the correlation between the dihydrouracil/uracil ratio (DUUR) and 5-FU pharmacokinetics, followed by the first attempt to adjust the 5-FU dose according to the pretreatment DUUR in plasma. Further investigation of the key role of the DUUR in 5-FU catabolism and curative effects to determine the individual 5-FU dose would be a critical strategy to improve fluoropyrimidine chemotherapeutic efficacy.
In this study, we applied 2 fluoropyrimidine drugs, 5-FU and floxuridine (FUDR), to study the relationships of plasma DUUR with the clinical pharmacokinetic parameters (area under the concentration-time curves [AUC], plasma clearance [CL]) and the corresponding therapeutic indexes (absolute neutrophil count [ANC], the decrease of human chorionic gonadotrophins [%
HCG/ß-HCG]). FUDR is a deoxyribonucleoside prodrug of 5-FU, which is mainly metabolized to 5-FU by thymidine phosphorylase (TP) in a fast first-order rate.21 To date, no data have been reported on the application of FUDR in GTT treatment or about the comparison of FUDR and 5-FU in pharmacokinetics and pharmacodynamics. Therefore, this study provides 3 aspects of clinical data: (1) the DUUR has an important role in marked interpatient variations of fluoropyrimidine pharmacokinetics and pharmacodynamics, (2) FUDR is not necessarily more potent than 5-FU in GTT treatment via 8-hour continuous infusion administration, and (3) the establishment of a dose adjustment chart is necessary to determine individual 5-FU doses by individual pretreatment DUUR.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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2; chemotherapy regimen completed at least 3 weeks before study enrollment and uracil concentrations in plasma below the physiology level of 100 ng/mL; clinical stage I/II according to Song diagnosis criteria* for trophoblastic tumor26 fit to conduct single 5-FU or FUDR treatments; blood indexes with blood plates 
100 x 109 cells/L, ANC > 1.5 x 109 cells/L, and hemoglobin 9 g/dL; and hepatic function that is total bilirubin 3 times the upper limit of normal. Other basic characteristics of the patients are listed in Table I. The decreases of HCG and ß-HCG prior to and after treatments (for the test cycle) were recorded as the indexes for estimating the decrease of trophoblast.
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Treatment Schedule
Single-dose 5-FU or FUDR chemotherapy was conducted in a daily dose of 30 mg/kg for 10 consecutive days. The drugs were dissolved in 500 mL of 5% dextrose and given by continuous intravenous infusion over 8 hours. During the treatments, toxic side effects were daily recorded, including vomiting times, mucous membrane toxicity, diarrhea, and so forth; the number of blood cells was measured every 2 to 3 days for monitoring the inhibition of bone marrow by the drugs. The levels of HCG and ß-HCG were examined prior to the treatment and after the 5 to 7 days of the complete cycle. The decreases of HCG and ß-HCG levels after treatments were used as the quantitative indexes for curative effects. A pelvic cavity examination, an abdominal computed tomography scan, a chest xray or computed tomography scan, and other appropriate diagnostic procedures to evaluate metastatic sites were performed after every cycle of treatment.
Pharmacokinetics
Blood samples were sampled on day 1 of the test cycle, using a peripheral catheter placed in a forearm vein at baseline; at 2, 4, 6, and 8 hours after the start of infusion; and at 10, 20, 30, 40, 60, and 120 minutes after the end of infusion. The samples were then immediately centrifuged (4°C, 3000 rpm), and the upper plasma was stored at -20°C until the assay for the concentrations of uracil, dihydrouracil, 5-FU, and FUDR was performed by a high-performance liquid chromatography/tandem quadrupole mass spectrometry system (HPLC-MS/MS) previously reported by our group.27 In brief, 200-µL plasma samples with the addition of a 100-µL internal standard solution (5-brominouracil, 400 ng/mL) were extracted with 5 mL of ethyl acetate-isopropanol (85:15, v/v) after 150 mg ammonium sulfate was added. The extraction mixture was vortexed for 1 minute at 800 rpm, followed by 20 minutes of extraction on the shaker. The upper organic phase was dried under 45°C nitrogen gas. The dried pellets at the bottom of the test tubes were redissolved in 100 µL of 10% methanol. Then, the 20-µL aliquot was injected into the HPLCMS/MS instrument for quantitation analyses. Standard chemicals were all purchased from Sigma (St Louis, Mo); the HPLC-MS/MS system consisted of a Model 510 HPLC system (Waters, Milford, Mass) and a PE SCIEX API 3000 triple quadrupole mass spectrometer with electrospray ion source (ESI). The chromatographic column conducting the analyses was a Discovery Amide C16 analytical column (4.6 x 150 mm ID, 5 µm; Supelco, Bellefonte, Pa). The analytes of uracil, dihydrouracil, 5-FU, and FUDR contained in plasma samples were separated with 3% methanol as the mobile phase at the flow rate of 1 mL/min (splitting ratio, 10:1) and consequently monitored by a mass spectrometer in the negative ESI multiple-reaction monitoring mode (uracil, m/z 110.9 
42.2; dihydrouracil, m/z 112.9 42.3; 5-FU, m/z 128.9 42.0; FUDR, m/z 245.1 42.0; and internal standard, 5-BU, m/z 188.9 42.0). Peak areas of uracil, dihydrouracil, 5-FU, and FUDR were normalized by the standard curves to the corresponding concentrations in plasma. The limits of the quantitation for uracil, dihydrouracil, 5-FU, and FUDR were 0.5, 5, 2.5, and 0.25 µg/L, respectively. The linear correlation coefficients (r) of the standard curves for the quantitation of uracil, dihydrouracil, 5-FU, and FUDR were > 0.9900. Validation tests showed that the accuracy (92%-110%) and precision (RSD < 10%) of the analytical method were qualified for the quantitation of uracil, dihydrouracil, 5-FU, and FUDR in plasma samples.
Statistical Analysis
The correlations between the DUUR, pharmacokinetic parameters, and efficacy indexes were determined by Pearson correlation coefficients. The level of significance was set at P .05. Analyses were performed with the Statistical Package for the Social Sciences 10.0 (SPSS Inc, Chicago, Ill). Pharmacokinetic parameters were obtained, followed by noncompartmental model analysis with WinNonlin (version 1.5, Scientific Consulting Inc, Cary, NC) pharmacokinetic analysis software, including areas under the curve (AUC), elimination coefficient (Ke), half-life (t1/2), plasma clearance (CL = dose/AUC).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics of 5-FU and FUDR
Significant variations of the maximum plasma 5-FU and FUDR concentrations (Cmax5-FU and CmaxFUDR) in 40 patients were observed (Tables II, III): a 10.2-fold difference of Cmax5-FU in the 5-FU group (357.4-3642.1 µg/L), a 9.1-fold difference of CmaxFUDR in the FUDR group (79.7-724.8 µg/L), and a 5.9-fold difference of metabolite Cmax5-FU in the FUDR group (57-338.2 µg/L). Significant differences in pharmacokinetic parameters were also observed: 10.3-fold and 7.9-fold differences of AUC5-FU and CL5-FU (AUC5-FU: 122.8-1258.7 mg • min/L; CL5-FU: 1.3-10.2 L/min), as well as 8.3-fold and 5.8-fold differences of AUCFUDR and CLFUDR (range, AUCFUDR: 29.3-243.7 mg • min/L; CLFUDR: 6.5-37.8 L/min). Mean plasma concentration-time curves of 5-FU, FUDR, and metabolite 5-FU indicated that 5-FU concentrations in the 5-FU group were significantly higher than that in the FUDR group (Figure 2). The sum of the AUCs (for FUDR and metabolite 5-FU) in the FUDR group is only 37.7% of AUC5-FU in the 5-FU group, which caters to the different metabolism modes of 5-FU and FUDR, as FUDR is mainly activated to 5-FU by TP before entering into 5-FU metabolic pathways.21 The corresponding clinical parameters for 5-FU and FUDR are shown in Table II and Table III.
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Correlations of Pretreatment DUUR With Pharmacokinetic Parameters
The administered 5-FU dose (in milligrams), distributed over a narrow range of 1100 to 1800 mg/day (Figure 3A, B), did not show any correlation with the corresponding AUC5-FU (P > .05) or CL5-FU (P > .05), indicating that the adjustment of administered dose with BW did not normalize the interpatient variations in 5-FU pharmacokinetics. However, correlation analyses indicated significant correlations between the DUUR and log-transferred AUC5-FU (r = -0.877, P < .01), as well as between the DUUR and plasma CL5-FU (r = 0.7877, P < .01) (Figure 3C, D). In the FUDR group, BW-adjusted dose (in milligrams) identically had no significant correlations with AUCFUDR (P > .05) and CLFUDR (P > .05) (Figure 4A, B), whereas the DUUR showed significant correlations with log-transferred AUCFUDR (r = -0.813, P < .01) and CLFUDR (r = 0.0824, P < .01) (Figure 4C, D). These results indicate that the difference in DUURs among patients is associated with marked variations in AUC5-FU and CL5-FU but not the different BWs.
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Correlations of Pretreatment DUUR With Efficacy Indexes
ANC is normally used as an important toxic index in clinical chemotherapies for estimating hematologic toxicity,28,29 while the decreases of HCG and ß-HCG levels are used as the efficacy indexes in GTT treatments.30,31 After treatments in the test cycle, the mean ANC level was higher in the 5-FU group (4.6 ± 1.4 x 109/L) than in the FUDR group (4.0 ± 1.9 x 109/L), but this difference was not statistically significant (P > .05; Tables II and III). In addition, mean decreases of HCG and ß-HCG in the 5-FU or FUDR group showed remarkable interpatient differences (Figure 5B, C and Figure 6B, C), indicating that dose adjustment with BW had little contribution to treatment efficacies. However, correlation analyses showed that the DUUR was significantly correlated with the ANC, %HCG, and %ß-HCG in the 5-FU and FUDR groups (P < .01; Figures 5, 6). These results proved that the DUUR, rather than body weight, is a key factor associated with the interpatient variations in toxicity and efficacy.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Because our previous study had proved the significant correlation between the DUUR and the DPD level,22 we speculated that the difference in the DUURs between these patients and healthy subjects (Figure 1) is consistent with the difference in PBMC-DPD levels. Etienne et al8 reported a population study of DPD in cancer patients indicating that the mean DPD activity in cancer patients (0.222 nmol/min/mg) was higher than that in healthy subjects (0.189 nmol/min/mg) reported by Lu et al.9 This study confirmed the significant difference of basal DUURs between cancer patients and healthy subjects (P < .01; Figure 1). The phenomenon that pyrimidine was more extensively catabolized by DPD in cancer patients than healthy subjects, which resulted in higher DUUR, might be explained as the higher DPD activity found in tumor tissues than in normal tissues.36-38 In other words, higher pyrimidine bioavailability in tumors39 would be the main contribution to the relatively higher DUURs in patients.
In this study, marked variations of drug pharmacokinetic parameters observed in patients, after they were administered with the same dose normalized with BW (in mg/kg), indicated that BW could not normalize the individual difference in 5-FU pharmacokinetics due to the fact that DPD is not the key determinant in 5-FU metabolism.9-14,16 Interestingly, the DUUR was significantly correlated with the corresponding pharmacokinetic parameters (AUC and CL), although the doses had been adjusted by BW individually in a narrow range (1100-1800 mg). Therefore, these findings proved our hypothesis that varied DPD levels or DUURs are the key factors for interpatient variations in 5-FU pharmacokinetics. The relationships of the DUUR with the corresponding %ANC and %HCG/ ß-HCG indicated that different responses among patients were associated with the differences in DUURs. ANC and HCG/ß-HCG levels are the sensitive and representative indexes for predicting main toxicities and efficacy; most important, they can be quantitatively evaluated and are superior to other clinical indexes.23-25 Furthermore, after comparing the clinical efficacy and toxicities between 5-FU and FUDR treatments in GTT patients, no obvious differences were found, which is consistent with the in vitro results.40
Chemotherapeutic efficacy is normally associated with dose intensity, which is defined as the amount of drug delivered per unit of time, regardless of the schedule used. A dose-intense regimen may or may not be associated with high peak drug levels, whereas continuous administration of chemotherapeutic regimens may be quite dose intensive due to the higher AUC for plasma pharmacokinetics. Therefore, control of AUCs in chemotherapy is a key point to ensure ideal efficacy. In this study, from Figures 5 and 6, we speculated that AUCs derived from DUUR = 2 are the optimal AUCs (effective AUCs) because significantly higher efficacy (%HCG/ß-HCG) and endurable toxicity (ANCs) were obtained when DUURs were about 2. Therefore, based on the formula Dose = AUC x CL, dose adjustment according to varied CLs will ensure that the resultant AUC is near to effective. Thus, based on the quantitative relationships of the DUUR with 5-FU/FUDR pharmacokinetics, the following formulas were developed:
Undoubtedly, the coefficients in the above equations would change as data from more patients are collected. However, this preliminary study proved our hypothesis that DUUR is a potential factor associated with the variations of clinical pharmacokinetics and pharmacodynamics in the standard treatment. This finding will provide more reasonable explanations for the following facts: (1) remarkable variation of pharmacokinetic parameters in fluoropyrimidine chemotherapies with standard identical doses is the result of varied DPD levels among patients. (2) This variation caused by the varied DPD levels could be reflected by a biomarker DUUR. (3) Modified doses of fluoropyrimidine drugs are required for patients with different expression of DPD instead of standard treatment, indicating that a reasonable index is necessary to quantitatively normalize doses according to the individual DPD levels.
In addition, overweight patients dosed at adjusted or ideal weight may be receiving insufficient treatment and therefore may be at greater risk for relapse, and underweight patients dosed at ideal weight may be overdosed and thus inclined to experience increased drug toxicity.41 Therefore, dose adjustments by varied DUURs and possible weight normalization were co-considered in this study, and thus BMI was incorporated into the dose adjustment charts. The daily net dose administered to patients was corrected by the percentage of standard BMI (ie, if the BMI of a patient is 90% of the standard BMI, the net dose would be the dose indicated in the theoretical dose charts multiplied by 90%). The theoretical dose adjustment charts produced are shown in Figure 7. In our view, patients with the DUUR beyond the range of 1 to 6 should be advised to apply other chemotherapeutic strategies because of unexpected severe toxicities (DUUR < 1) and drug resistances (DUUR > 6). In summary, this dose adjustment regime will ensure that a higher dose of the drug is administered to patients with a higher DPD level, catering to the higher bioavailability of fluoropyrimidines, and also will reasonably decrease the administered dose for patients with partial DPD deficiency to avoid severe toxicities. This dose adjustment chart is being validated in a phase II study in our hospital.
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FOOTNOTES |
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* Stage-I tumor is confined to the uterine cavity and uterine body; stage-II tumor includes local metastases to the pelvis (IIa) or vagina (IIb); stage-III tumor involves pulmonary metastases (IIIa: less than 50% lung opacification, IIIb: more than 50% lung opacification); stage-IV tumor involves distant metastases including liver, brain, bowel, kidneys, spleen, etc. 
Submitted for publication February 8, 2004; Revised version accepted July 5, 2004.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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