PubMed Health⌕ Search

Biomedical subjects

M C Etienne

Publications and source records attributed to M C Etienne.

At least 55 records · Page 3Linked to original sources
PubMed1995

[Population study of dihydropyrimidine dehydrogenase in cancer patients].

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme of 5-fluorouracil (5-FU) catabolism. The clinical importance of DPD has recently been demonstrated with the identification of severe and/or lethal 5-FU-related toxicity in patients with suspected or proven DPD deficiency revealed in lymphocytes. We conducted a prospective study on 185 cancer patients in order to evaluate the incidence of complete or partial DPD deficiency. The population comprised 152 men (mean age 62.1) and 33 women (mean age 59.2). Sixty eight were head and neck patients treated by a 5-day continuous infusion of 5-FU (starting dose 1 g/m2/day, with dose adaptation at mid-cycle) for which DPD activity was measured 2-3 days before 5-FU administration (94 cycles analyzed). DPD activity was measured by a radioenzymatic assay using 14C-5-FU. DPD activity showed a unimodal distribution, which globally fits a Gaussian distribution. Mean and median DPD activity were 0.222 and 0.211 nmol/min/mg prot respectively (range 0.065-0.559). No total DPD deficiency was found. Neither liver function nor age influenced DPD activity, but DPD activity was on average 15% lower in women than in men (0.194 and 0.228 nmol/min/mg prot respectively, p = 0.03). In patients treated with 5-FU, the risk of developing side effects was not linked to pretreatment DPD activity. 5-FU-related toxicity was linked to FU systemic exposure. The correlation between DPD activity and FU clearance was weak (n = 90, r = 0.31, p = 0.002). As a corollary, DPD activity in patients requiring a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. From the present study it appears that total DPD deficiency is a very rare event. Although pre-treatment DPD activity cannot be a useful indicator for improving 5-FU dose adaptation strategy, the identification of partial DPD deficiency (< 0.100 nmol/min/mg prot, 3% of the population) could lead to starting the treatment with a markedly reduce 5-FU dose.

Adult↗
PubMed1995

Dihydropyrimidine dehydrogenase: a tumoral target for fluorouracil modulation.

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism. Ethynyluracil (776C) is a very potent, mechanism-based irreversible DPD inhibitor that improves the antitumor efficacy and the therapeutic index of FU in laboratory animals. We tested the cytotoxic effects of the FU-776C combination on a panel of 12 human cancer cell lines (4 breast, 4 head and neck, 3 colon, and 1 duodenum). Basal DPD activity (radioenzymatic assay) and FU sensitivity [FU 50% inhibitory concentration (IC50), 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test] were determined. The FU potentiation by 776C was calculated from the ratio (F) of FU IC50 without 776C divided by FU IC50 with 776C. 776C was not cytotoxic to any of the cell lines tested. On CAL51 cell line expressing a high basal DPD activity, FU enhancement by 776C was a saturable phenomenon related to the 776C concentration; the inhibition of DPD increased between 10(-12) to 10(-6) M of 776C. For the following studies, 776C was tested at 10(-6) M. FU IC50 varied from 15 to 7770 microM among cell lines (median, 390 microM). Basal DPD activity ranged from not detectable (< pmol/min/mg protein) to 320 pmol/min/mg protein among cell lines (median, 53 pmol/min/mg protein). For the 12 cell lines tested, the mean F ranged from 0.7 (no enhancement of FU cytotoxicity by 776C) up to 5.2 and was significantly related to the basal DPD activity: the greater the DPD activity, the greater the FU enhancement factor (Spearman rank correlation, P = 0.019). Enhancement of FU cytotoxicity by 776C occurred only in the six cell lines expressing the greatest basal DPD activity (>50 pmol/min/mg protein, F ranging between 1.7 and 5. 2), whereas 776C did not modify FU cytotoxicity in the remaining cell lines expressing the lowest DPD activity (<50 pmol/min/mg protein, F ranging between 0.7 and 1.4). F was significantly different between these two groups of cell lines (P = 0.005). These results point out that DPD is an interesting target for FU pharmacomodulation.

Antimetabolites, Antineoplastic↗
PubMed1994

Inhibition of dihydropyrimidine dehydrogenase by alpha-interferon: experimental data on human tumor cell lines.

Interferons (IFNs) are very promising fluorouracil (FU) biochemical modulators. The pharmacological origin sustaining the FU-IFN synergistic interaction is not clearly understood. It was recently shown that alpha-IFN was associated with a dose-dependent decrease in FU clearance in treated patients. Dihydropyrimidine dehydrogenase (DPD) is the key regulating enzyme for FU catabolism. The effects on DPD exerted by both the IFN dose and the duration of exposure were evaluated in a panel of five human cancer cell lines. All cell lines investigated exhibited quantifiable DPD activity with inter-cell-line variability (0.118-0.318 nmol min-1 mg protein-1). A prolonged exposure to IFN (up to 5 days) was necessary to obtain a significant inhibition of DPD activity. A concentration-dependent significant decrease in DPD activity, reaching 50% of the initial activity determined for the highest IFN concentration (10(5) IU/ml), was demonstrated in all cell lines tested (5-day IFN exposure). For three cell lines, IFN potentiated the FU-induced growth inhibition in a concentration-dependent manner. Considering all cell lines and all IFN concentrations, it appears that globally, the greater the inhibition of DPD activity, the greater the FU potentiation (Spearman rank correlation on all cell lines, P = 0.011).

Carcinoma↗
PubMed1994

A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil.

Despite being one of the oldest anti-cancer drugs, fluorouracil (FU) is still being increasingly used in cancer chemotherapy. The source of variability for FU sensitivity in patients may be complex, although an overproduction of thymidylate synthase (TS) was the only mechanism of resistance identified in tumours from FU-resistant patients. Dihydropyrimidine dehydrogenase (DPD) is the first and rate-limiting enzyme of FU catabolism. Thus, DPD activity may be a potential factor for controlling FU responsiveness. A panel of 19 human tumour cell lines, including digestive tract, breast and head and neck cancer cells, were investigated. Both TS and DPD activities were measured in parallel to FU responsiveness. None of the cell lines had been previously exposed to FU, and thus expressed a spontaneous sensitivity to FU. Sensitivity between cell lines showed marked differences, with IC50 values ranging from 45 ng/ml (colon cell line) to 5063 ng/ml (head and neck cell line). TS activity was measurable in all cell lines and varied within a 46-fold range. DPD activity was detected in all but four cell lines, showing a 100-fold range of variation. Cell lines most sensitive to FU exhibited the lowest DPD and TS activities and vice versa. Simple linear regression analysis showed that both TS (r2 = 0.22, P = 0.042) and DPD (r2 = 0.27, P = 0.022) activities were significantly correlated to FU effectiveness (log 10 IC50): the greater the enzyme activities, the higher the FU IC50. TS and DPD were demonstrated to be independent variables. A multiple regression analysis showed that the combination of TS and DPD activities explained 36% of the variability in FU IC50 (r2 = 0.36, P = 0.01). Two groups of cell lines could be identified, one group with both low TS and low DPD activities (G1), and the other with either high TS and/or high DPD activities (G2). Mean FU IC50 values were 193 and 930 ng/ml in G1 and G2, respectively, and this difference in FU sensitivity was highly significant (P = 0.009). The present study shows, for the first time, that DPD activity in tumour cells is an independent factor significantly related to FU sensitivity. These results should encourage DPD and TS coupled measurements in tumours of patients before FU treatment in order to establish their prognostic relevance. DPD and TS measurements could also be used during the treatment course to determine the implication of these enzymes in the development of tumour resistance to FU.

Breast Neoplasms↗
PubMed1994

Cytotoxic effects of long-term circulating ultrafiltrable platinum species and limited efficacy of haemodialysis in clearing them.

We applied haemodialysis to clear platinum (Pt) circulating species following renal insufficiency due to an accidental cisplatin overdosage (205 mg/m2 instead of 100 mg/m2). Serum samples were repeatedly obtained during this clinical episode from day 5 up to day 30 after cisplatin dosing. A serum aliquot taken at day 22 after cisplatin administration was tested to assess the possible cytotoxicity exhibited by the circulating Pt species on a head and neck tumour cell line. The profile of ultrafiltrable (UF) Pt during successive haemodialysis cycles was striking. After each haemodialysis cycle, a marked decrease in UF Pt, occurred but was followed by more or less pronounced rebounds. Cisplatin concentration-cytotoxic effect curves obtained in vitro from patient serum before cisplatin administration and healthy control serum exhibited very similar concentration effect profiles. In contrast, the patient serum taken at day 22 after cisplatin administration resulted in marked cytotoxic effects, which were much greater than those which could have been anticipated considering the Pt concentration of this serum sample. The present report underlines the limited usefulness of haemodialysis for rescuing cisplatin treated patients, exhibiting unanticipated postinfusion renal failure with overexposure to the drug. The in vitro investigations suggest that pharmacological effects of Pt derivatives may not only be attributable to short-term effects of the drug diffusion into tissues, but also to more delayed effects from Pt circulating species.

Adenocarcinoma↗
PubMed1994

Wide range for optimal concentration of folinic acid in fluorouracil modulation--experimental data on human tumour cell lines.

The clinical use of the fluorouracil (FU)-folinic acid (FA) combination is hampered by the still open choice of the optimal schedule, with marked controversy as concerns the optimal FA dose. This in vitro study on FU-FA combinations in 17 human cancer cell lines, representative of tumour types responding to FU-FA treatment, reassesses the notion of the optimal FA concentration. Cells were exposed for 5 days to various FU-FA concentrations (0.07-77 microM, 14 concentrations, for FU; and 0.0025-100 microM for FA). The growth inhibition was assessed by the MTT test. The investigated cell lines exhibited FU IC50 ranging from 0.4 to 38.9 microM (median 3.7 microM). In six out of 17 cell lines investigated, the addition of FA did not result in a substantial enhancement of FU cytotoxicity (group 1). For the remaining 11 cell lines responding to FA supplementation (group 2), the maximal enhancement factor ranged from 3 to 8, meaning that in the presence of optimal FA concentration, the efficient FU concentration (IC50) was reduced by between 3 and 8 as compared to the efficient FU concentration without FA supplementation. For cell lines responding to FA supplementation, the optimal FA concentrations ranged from 10(-7) to 4 x 10(-4) M (4000-fold range) with a median value at 9.6 x 10(-7) M. Distribution of cell doubling time was not significantly different between group 1 and group 2. In contrast, the FU IC50 were significantly different (P = 0.02) between group 1 (median 7.4 microM) and group 2 (median 2.2 microM), thus indicating that cell lines with the greatest FU cytotoxicity enhancement by FA were those intrinsically sensitive to FU and vice versa.

Breast Neoplasms↗
PubMed1994

[Evolution from pharmacokinetics to pharmacogenetics. The example of 5-fluorouracil].

5FU tends to be used more and more frequently; this fact can be explained by its modulation, mainly by folinic acid. Pharmacokinetic follow-up of 5FU with dose adaptation has demonstrated its clinical usefulness by reducing significantly drug side-effects without any impairment in tumor response. Whatever the anticancer drug considered, it is theoretically possible to predict individual capacities for clearing it. This possibility has been explored for 5FU. Among the different tested variables only gender has a determined influence with females showing an average 15% reduction in 5FU clearance as compared to males. Age, hepatic function, nutritional status have no clear influence on 5FU clearance. 5FU catabolism is governed by a key enzymatic step involving dihydropyrimidine dehydrogenase (DPD). Recent case reports have shown that patients with partial or total DPD deficiency shown in lymphocytes were exhibiting severe 5FU related toxicities. A positive and significant correlation has been established between 5FU clearance and DPD activity measured in lymphocytes. This correlation is too weak for allowing individual 5FU dose to be calculated on the basis of lymphocyte DPD activity. Nevertheless DPD determination may allow high risk patients, with partial or total DPD deficiency to be identified.

Female↗
PubMed1994

Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer.

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 pm and peak of 5-fluorouracil and folinic acid at 4 am. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 pm, and maximum 5-fluorouracil and folate concentrations near 4 am. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 am (approximately 800 ng/ml) and a trough at 1 pm (approximately 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 am, trough near 6 pm, and amplitude approximately 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.

Adult↗
PubMed1994

Population study of dihydropyrimidine dehydrogenase in cancer patients.

PURPOSE: We conducted a prospective study on a large set of cancer patients in an attempt to evaluate the incidence of complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency as found in peripheral mononuclear cells (PMNC). PATIENTS AND METHODS: One hundred eighty-five unselected consecutive cancer patients were included. The population consisted of 152 men (mean age, 62.1 years; range, 35 to 90) and 33 women (mean age, 59.2 years; range, 36 to 77). Sixty-eight were head and neck patients treated by a 5-day continuous infusion of fluorouracil (FU; starting dose, 1 g/m2/d, with dose adaptation based on pharmacokinetics) for which DPD activity was measured 2 to 3 days before FU administration (94 cycles analyzed). PMNC-DPD activity was measured by a radio-enzymatic assay using carbon-14-FU. RESULTS: DPD activity in the entire population showed a unimodal distribution, which globally fits a gaussian distribution. Mean and median DPD activity values were 0.222 and 0.211 nmol/min/mg protein, respectively (range, 0.065 to 0.559). No total DPD deficiency was found. Multifactor analysis of variance showed that liver function (biologic evaluation) and age did not influence DPD activity, but that DPD activity was, on average, 15% lower in women (0.194 nmol/min/mg protein) than in men (0.228 nmol/min/mg protein) (P = .03). No difference was demonstrated between premenopausal and postmenopausal women. In patients treated with FU, the risk of developing side effects was not linked to pretreatment DPD activity. FU-related toxicity was linked to FU systemic exposure. The correlation between pretreatment DPD activity and FU systemic clearance (CI) was weak (n = 90, linear regression r = .31, P = .002). Pretreatment DPD activity in patients who required a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. CONCLUSION: From the present study, it appears that total DPD deficiency is a rare event. Although pretreatment DPD activity cannot be a useful indicator for improving FU dose adaptation strategy, the identification of severe DPD deficiency (< 0.100 nmol/min/mg protein) could lead to starting the treatment with a markedly reduced FU dose or even to using an alternative chemotherapy regimen.

Adult↗
PubMed1994

Relationship between fluorouracil systemic exposure and tumor response and patient survival.

PURPOSE: The aim of this study was to analyze the link between fluorouracil (FU) systemic exposure and tumor response and overall survival. PATIENTS AND METHODS: One hundred eighty-six patients (162 men, 24 women) with head and neck cancer were studied. All received cisplatin plus FU for three cycles as first-line chemotherapy. The treatment consisted of cisplatin (100 mg/m2 intravenously [IV]) followed by a 5-day continuous venous infusion of FU (1 g/m2/d). The median follow-up duration for the 104 patients alive was 24 months. For each cycle, we calculated the area under the curve over the duration of pharmacokinetic follow-up (AUC0-105 h) for plasma FU. For each patient, we analyzed the averaged AUC0-105 h and the averaged total dose for the three cycles. RESULTS: The response rate was 30% complete responses (CRs), 22% partial responses (PRs) more than 75%, 25% PRs less than 75%, and 23% no response (NR). Medians for averaged AUC and dose per cycle were 27,906 ng/mL h (first through third quartile, 25,398 to 31,060) and 7,000 mg (first through third quartile, 6,200 to 7,833), respectively. The tumor response was significantly linked to tumor stage (P < .001) and to averaged AUC (P = .05), but not to averaged dose. Analysis of parameters (continuous variable) expressing FU treatment intensity showed that dose did not influence survival contrary to the AUC (P = .001). The AUC remains significant (P = .025) in a multivariate analysis including tumor stage, demonstrating that the greater the FU systemic exposure, the longer the survival. CONCLUSION: These results strengthen the interest of individual FU dose adaptation based on pharmacokinetics.

Adult↗
PubMed1993

Combination of reduced folates with methotrexate or 5-fluorouracil. Comparison between 5-formyltetrahydrofolate (folinic acid) and 5-methyltetrahydrofolate in vitro activities.

Folinic acid (dlFA) is increasingly used in clinical oncology. The active isomer lFA is intensively metabolized into l5-methyltetrahydrofolate (l5MTHF), the relative proportions of lFA, dFA and l5MTHF in blood varying considerably between oral and i.v. FA administration. The purpose of the study was to compare the in vitro activities of pure lFA and pure l5MTHF at equivalent drug exposure [area under curve (AUC)], taking into account their respective chemical stability in the culture medium. The in vitro growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test] was evaluated on five human tumor cell lines after methotrexate (MTX)-folate or 5-fluorouracil (5FU)-folate exposures. Not only were the activities of lFA and l5MTHF compared, but also clinically relevant mixtures of lFA + dFA + l5MTHF corresponding to the proportions found at steady state during oral (PO mixture, 4, 39 and 57%, respectively) and i.v. administrations (i.v. mixture, 7, 81 and 12%, respectively). Measurement of folates demonstrated the marked lability of l5MTHF (65.8% loss over 5 days in the culture medium) as compared to lFA (2.6% loss). Whatever the pharmacological model tested (MTX-folate or 5FU-folate), comparison of the folate effects at equivalent drug exposure taking into account their relative stability showed that l5MTHF was never more potent than lFA. Moreover, a higher efficiency of lFA was demonstrated for the cell line most sensitive to 5FU; in this case, as expected, the i.v. mixture was more potent than the PO mixture. This study shows that depending on the tumor, lFA can be more potent than its main circulating metabolite l5MTHF. Along with the limited capacity of oral absorption, the choice between oral and i.v. route for FA administration in patients should take into consideration the different pharmacological activities between lFA and l5MTHF which suggest that the oral route is potentially detrimental to the optimal activity of the 5FU-FA combination as compared to i.v. administration.

Antineoplastic Agents↗
PubMed1993

[l-folinic acid versus racemic folinic acid in the treatment of leukemia in children with high dose of methotrexate].

Until now, folinic acid (FA) has been available the racemic mixture d1 FA, whose biological activity is supported by natural 1 FA. The purpose of this trial was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture dl FA with the pure 1 FA in the rescue of high-dose methotrexate (MTX) therapy. Eighteen children with acute lymphocytic leukemia (ALL) were entered in this trial planned with a cross-over design. Four cycles of MTX (5 g/m2, 24h CVI) were administered to each patient, with a 2-week interval between cycles. The rescue was achieved orally every 6h, starting 12h after the end of the MTX infusion, at a dose of 12 mg/m2 for dl FA and 6 mg/m2 for pure 1 FA. dl FA and 1 FA rescues were alternated from one cycle to the next. d FA, 1 FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific HPLC assay. After administration of dl FA, the accumulation of d FA in plasma was confirmed: mean residual concentrations were 420 and 652 nM after 2 and 6 intakes respectively. Total active folate concentrations (1 FA + 5-MTHF) were similar between the two types of rescue: 92 and 100 nM respectively for dl FA rescue and 1 FA rescue after two intakes, 186 and 184 nM respectively for dl FA rescue and 1 FA rescue after six intakes. Intra-individual statistical analysis of total active folates (1 FA + 5-MTHF) performed on 17 patients did not show any significant difference between dl FA rescue and 1 FA rescue. For both types of rescue, MTX terminal half-lives were identical (average value 13.9 h). Considering each type of toxicity (hematologic, hepatic, renal and digestive) there was no significant difference in the proportion of toxic cycles following l FA rescue or dl FA rescue. In conclusion, the administration of the pure l FA, as compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, and leads to equivalent treatment tolerance.

Adolescent↗
PubMed1993

[Clinical pharmacokinetics and practical consequences of optimal use of medroxyprogesterone acetate].

Medroxyprogesterone acetate (MPA) is one of the major drugs used in endocrine therapy for advanced breast cancer. However, its optimal dose is still not clearly established. Response to treatment and drug-related side effects were analyzed as a function of plasma MPA concentrations during prolonged MPA administration. MPA plasma concentrations were measured (HPLC assay) at steady state (Css min) in 129 patients (mean age 63 years, 34-87) treated by MPA (111 being treated orally exclusively, with daily doses ranging from 400 to 2000 mg). A wide inter-patient variability was noted in MPA Css min for the 70 patients receiving 1000 mg/day per os: median 51 ng/ml, range 10-269 ng/ml. Intra-patient analysis of the evolution of MPA Css min during prolonged treatment showed relative stability of MPA concentrations (mean coefficient of variation = 21%). A weak but nevertheless significant correlation was demonstrated between oral doses and MPA Css min (P = 0.016). Thirty-five percent of patients (45/129) developed MPA-related side effects which were associated with the highest plasma MPA concentrations: medians were 81 and 32 ng/ml for toxic and non-toxic treatments respectively (P < 0.001). Moreover, the cumulative incidence of side-effects constantly increases with the elevation of Css min. Objective response was assessable in 55 patients treated by MPA exclusively. Plasma MPA concentrations were significantly different between patients with PD and those with either CR, PR or SD: medians were 46 and 65 ng/ml respectively (P = 0.025). The cumulative incidence of objective response increases up to 70 ng/ml. Analysis of toxicity and response as a function of the oral dose did not reveal any significant relationship. These data suggested an optimal therapeutic window for MPA Css min located within 50-70 ng/ml. This study demonstrates that, as opposed to the administered dose, plasma MPA concentration is a determining factor for toxicity and response to therapy.

Adult↗
PubMed1993

HPLC of folinic acid diastereoisomers and 5-methyltetrahydrofolate in plasma.

We present a rapid, sensitive, and automated HPLC method with direct resolution of l-folinic acid (l-FA), d-folinic acid (d-FA), and 5-methyltetrahydrofolate (5MTHF) from plasma samples. Plasma (500 microL) is first extracted on solid phase (RP-18 cartridge). The dI-FA peak is collected on-line from a reversed-phase column (RP-8, 119 x 2 mm, 4 microns: HPLC 1) and then automatically loaded onto a chiral stationary phase (human serum albumin, 150 x 4.6 mm, 7 microns: HPLC 2). The same mobile phase flows in both systems (0.2 mol/L Na2HPO4:1-propanol, 98:2, pH 6.2). HPLC 1 allows quantification of 5MTHF by absorption at 313 nm; HPLC 2, the quantification of l-FA and d-FA by electrochemical detection in the oxidation mode (total run time 18 min). Recoveries are > 80%. CVs for intra- and interassay reproducibilities are < 5% and 15%, respectively. Linearity of the response (0.1-1 mumol/L and 1-50 mumol/L, r = 0.99, P < 0.01) is satisfactory. The sensitivity limit is 50 nmol/L for 5MTHF and 20 nmol/L for l-FA and d-FA. This assay is substantially improved over existing methods regarding feasibility and is being used in pharmacokinetic investigations in cancer patients.

Acetaminophen↗
PubMed1992

l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children.

BACKGROUND: At this time, folinic acid (FA) is commercially available as the racemic mixture d,l-FA, whose biological activity is supported by natural l-FA. The administration of d,l-FA results in the accumulation of d-FA in plasma relative to the active l-FA form; in vitro studies have shown that d-FA can compete with the polyglutamation of methotrexate (MTX). PURPOSE: Our purpose was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture d,l-FA with the pure l-FA in rescue of high-dose MTX therapy (5 g/m2) in children with acute lymphocytic leukemia (ALL). METHODS: Eighteen children with ALL were entered in this trial, which was planned with a crossover design. Four cycles of MTX were administered to each patient, and rescue was achieved orally every 6 hours at a dose of 12 mg/m2 for d,l-FA and 6 mg/m2 for pure l-FA. The d,l-FA and l-FA rescues were alternated from one cycle to the next. d-FA, l-FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific high-performance liquid chromatography assay. RESULTS: Considering total active folate levels (l-FA + 5-MTHF), mean residual concentrations were similar for rescue by d,l-FA and l-FA, after two and six intakes, respectively: 92 and 186 nM for d,l-FA rescue versus 100 and 184 nM for l-FA rescue. Intra-individual comparison of total active folates (l-FA + 5-MTHF) did not show any significant difference between d,l-FA rescue and l-FA rescue. After administration of d,l-FA, the accumulation of d-FA in plasma was confirmed. For both types of FA rescue, MTX terminal half-lives were identical (average value, 13.9 hours). Considering each type of toxic effect (hematologic, hepatic, renal, and digestive), there was no significant difference in the proportion of toxic cycles following l-FA rescue or d,l-FA rescue. CONCLUSION: The administration of the pure l-FA, compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, leads to equivalent treatment tolerance, and avoids the plasma accumulation of d-FA.

Adolescent↗
PubMed1992

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.

Adult↗