ABSTRACT
OBJECTIVES: Patients with Parkinson disease exhibit a highly increased prevalence of small intestinal bacterial overgrowth (SIBO), which has been also associated with the severity of motor fluctuations. Aim of this study was to test the efficacy of liquid levodopa with higher bioavailability in patients with SIBO. METHODS: Thirty-three patients with Parkinson disease underwent both lactulose and glucose breath tests to assess the presence of SIBO. A urea breath test was performed to assess the presence of a concomitant Helicobacter pylori infection. Patients were challenged with 250 mg of levodopa and 314 mg of levodopa methylester. Drug challenges were performed on different days and at baseline and 1 month after SIBO eradication. During the tests, the motor condition and the plasma levodopa concentrations were evaluated. RESULTS: At baseline, the onset of motor benefit was significantly shorter after melevodopa than after standard levodopa, as confirmed by the latency to motor on condition and t max (time to the on condition, 28.8±11.5 vs 55.5±40.2 minutes; P=0.0004; and t max, 28.2±9.7 vs 50.0±11.0 minutes; P=0.002). The duration of the on time or area under the curve was not significantly different. The underlying gastrointestinal condition did not influence these results. CONCLUSIONS: The reduction of the latency to the on condition in the absence of a reduction of the on duration is a promising feature of melevodopa because this effect would increase the total daily on duration. Future studies that evaluate the usefulness of melevodopa beyond the acute challenge (eg, using motor diaries) in patients with gastrointestinal infections are warranted.
Subject(s)
Helicobacter Infections/epidemiology , Helicobacter pylori/pathogenicity , Levodopa/analogs & derivatives , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Aged , Analysis of Variance , Antiparkinson Agents , Breath Tests , Female , Gastrointestinal Agents/therapeutic use , Glucose/metabolism , Helicobacter Infections/diagnosis , Helicobacter Infections/drug therapy , Humans , Lactulose/metabolism , Male , Middle Aged , Parkinson Disease/epidemiology , Rifamycins/therapeutic use , Rifaximin , Severity of Illness IndexABSTRACT
OBJECTIVES: It has been previously shown that the treatment with the two protease inhibitors APG12 and APG19 confers protection in a rat model of mucosal candidiasis; in this study, we examined whether these peptidomimetic inhibitors are also effective as a cream formulation in reducing Candida albicans vaginal infection. METHODS: These efficacy studies were performed in a rat model of estrogen-dependent rat vaginitis by C. albicans on both azole-susceptible and azole-resistant C. albicans, and on both caspofungin-susceptible and caspofungin-resistant C. albicans strains. In vivo studies were also conducted in female albino rats and rabbits to obtain information about the safety, local tolerability and principal pharmacokinetics parameters of the two compounds. KEY FINDINGS AND CONCLUSIONS: Both hit compounds showed remarkable results within the 48-h range as effective inhibitors of the infection, particularly causing rapid decay of vaginal C. albicans burden. Importantly, the two compounds showed marked acceleration of fungus clearance in the rats challenged with the fluconazole-resistant as well as with the capsofungin-resistant strain of C. albicans. Both compounds showed fast elimination rates when given by the intravenous route, and poor systemic absorption after intravaginal cream administration. Test drugs were also well tolerated in 7-day local tolerability experiments in the rabbit.
Subject(s)
Aspartic Acid Proteases/antagonists & inhibitors , Candida albicans/drug effects , Candidiasis/drug therapy , Peptidomimetics/pharmacology , Peptidomimetics/pharmacokinetics , Vaginal Creams, Foams, and Jellies/pharmacology , Vaginal Creams, Foams, and Jellies/pharmacokinetics , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Caspofungin , Chemistry, Pharmaceutical/methods , Echinocandins/pharmacokinetics , Echinocandins/pharmacology , Female , Fluconazole/pharmacokinetics , Fluconazole/pharmacology , Lipopeptides , Rats , Rats, Wistar , Vaginitis/drug therapyABSTRACT
Therapeutic drug monitoring of raltegravir Ctrough levels was carried out in the setting of the Raltegravir Switch for Toxicity or Adverse events (RASTA) trial, a randomized pilot study exploring a 48-week safety and efficacy of treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virologic control. Blood sampling for measurement of raltegravir plasma levels was carried out at weeks 4, 12, 24, 36 and 48. Plasma samples were analysed by a recently developed and validated UPLC-MS method. A total of 164 samples from 39 patients were assayed. Analysis for intra- and inter-subject variability was restricted to those patients with 4 or more determinations, including 30 patients and 142 determinations. The intra- and inter-subject variability measures were 85.9 and 124.6%, respectively, with an intra-/inter-subject variability ratio of 69%. We also analysed data from a subset of patients with well-documented adherence to protocol, defined as protocol compliant population, including 21 patients and 93 determinations. In this subpopulation, we estimated intra- and inter-subject variability of 79.87% and 110%, respectively, with an intra-/inter-subject variability ratio of 72.6%. This study confirms the notion that raltegravir is a highly variable drug according to the European Medicines Agency criteria. While this condition does not favour the adoption of therapeutic drug monitoring in the clinical practice, the latter is deemed useful in patients with drug plasma concentrations below or near the threshold level of efficacy (since intracellular raltegravir levels might be as low as 5% of the corresponding plasma levels), or to identify drug-drug interactions of potential clinical relevance.
Subject(s)
Anti-HIV Agents/blood , HIV Infections/blood , Pyrrolidinones/blood , Adenine/administration & dosage , Adenine/analogs & derivatives , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Dideoxynucleosides/administration & dosage , Drug Combinations , Emtricitabine , HIV Infections/drug therapy , Humans , Lamivudine/administration & dosage , Organophosphonates/administration & dosage , Pyrrolidinones/administration & dosage , Pyrrolidinones/pharmacokinetics , Raltegravir Potassium , TenofovirABSTRACT
A rapid and selective HPLC-UV method was developed for the quantification of linezolid (LNZ) in human plasma and bronchoalveolar lavage (BAL) at the concentrations associated with therapy. Plasma samples were extracted by solid-phase extraction followed by evaporation to dryness and reconstitution in mobile phase solution. The chromatographic separation was carried out on a C18 column with an isocratic mobile phase consisting of dihydrogen phosphate buffer 50 mm (pH 3.5) and acetonitrile (60:40 v/v). The detection was performed using a photodiode array. Under these conditions, a single chromatographic run could be completed within 12 min. The method was validated by estimating the precision and the accuracy for inter- and intra-day analysis in the concentration range of 25-25600 ng/mL. The method was linear over the investigated range with all the correlation coefficients R > 0.999. The intra- and inter-day precision was within 8.90% and the accuracy ranged from -4.76 to +5.20%. This rapid and sensitive method was fully validated and could be applied to pharmacokinetic study for the determination of LNZ levels in human plasma and BAL samples.
Subject(s)
Acetamides/analysis , Acetamides/blood , Anti-Infective Agents/analysis , Anti-Infective Agents/blood , Bronchoalveolar Lavage Fluid/chemistry , Chromatography, High Pressure Liquid/methods , Oxazolidinones/analysis , Oxazolidinones/blood , Chromatography, High Pressure Liquid/economics , Drug Monitoring/economics , Drug Monitoring/methods , Humans , Limit of Detection , Linezolid , Solid Phase Extraction/economics , Solid Phase Extraction/methods , Spectrophotometry, Ultraviolet , Time FactorsABSTRACT
Parkinson's disease is associated with gastrointestinal motility abnormalities favoring the occurrence of local infections. The aim of this study was to investigate whether small intestinal bacterial overgrowth contributes to the pathophysiology of motor fluctuations. Thirty-three patients and 30 controls underwent glucose, lactulose, and urea breath tests to detect small intestinal bacterial overgrowth and Helicobacter pylori infection. Patients also underwent ultrasonography to evaluate gastric emptying. The clinical status and plasma concentration of levodopa were assessed after an acute drug challenge with a standard dose of levodopa, and motor complications were assessed by Unified Parkinson's Disease Rating Scale-IV and by 1-week diaries of motor conditions. Patients with small intestinal bacterial overgrowth were treated with rifaximin and were clinically and instrumentally reevaluated 1 and 6 months later. The prevalence of small intestinal bacterial overgrowth was significantly higher in patients than in controls (54.5% vs. 20.0%; P = .01), whereas the prevalence of Helicobacter pylori infection was not (33.3% vs. 26.7%). Compared with patients without any infection, the prevalence of unpredictable fluctuations was significantly higher in patients with both infections (8.3% vs. 87.5%; P = .008). Gastric half-emptying time was significantly longer in patients than in healthy controls but did not differ in patients based on their infective status. Compared with patients without isolated small intestinal bacterial overgrowth, patients with isolated small intestinal bacterial overgrowth had longer off time daily and more episodes of delayed-on and no-on. The eradication of small intestinal bacterial overgrowth resulted in improvement in motor fluctuations without affecting the pharmacokinetics of levodopa. The relapse rate of small intestinal bacterial overgrowth at 6 months was 43%. © 2013 Movement Disorder Society.
Subject(s)
Enteritis/complications , Helicobacter Infections/complications , Helicobacter Infections/epidemiology , Intestine, Small/microbiology , Parkinson Disease/complications , Aged , Analysis of Variance , Breath Tests , Disease Eradication , Enteritis/epidemiology , Enteritis/prevention & control , Female , Gastric Emptying , Gastrointestinal Motility/physiology , Glucose/metabolism , Humans , Intestine, Small/physiopathology , Male , Middle Aged , Parkinson Disease/epidemiology , Parkinson Disease/prevention & control , beta-Galactosidase/metabolismABSTRACT
BACKGROUND: An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the quantification of raltegravir (RTG) plasma concentrations in samples from HIV patients treated with the drug. METHODS: Plasma samples were extracted by liquid-liquid extraction followed by evaporation to dryness and reconstitution in mobile phase. The chromatographic separation was carried out on an AQUITY UPLC C18 column with an isocratic mobile phase consisting of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid (50:50 vol/vol). The detection was performed on a triple quadrupole tandem mass spectrometer using multi-reaction monitoring via electrospray ionization source with positive ionization mode. RESULTS: Under these conditions, a single chromatographic run could be completed within 1 minute. The method was validated by estimating the precision and the accuracy for inter- and intra-day analysis in the concentration range of 5-2560 ng/mL. The method was linear over the investigated range with all the correlation coefficients, r, greater than 0.995 on 5 replicates. The intra- and inter-day precision (percentage of coefficient of variation) ranged from 2.4% to 11.2%, and the inaccuracy (percent of relative standard deviation) ranged from 2.5% to 12.9%. No significant matrix effect was observed. The mean recovery value of RTG was 80%. CONCLUSIONS: This rapid and sensitive method was validated and could be applied to pharmacokinetic studies for the determination of RTG concentrations in human plasma samples.
Subject(s)
Liquid-Liquid Extraction/standards , Pyrrolidinones/blood , Tandem Mass Spectrometry/standards , HIV Infections/blood , Humans , Liquid-Liquid Extraction/methods , Raltegravir Potassium , Tandem Mass Spectrometry/methodsABSTRACT
Essential thrombocythemia (ET) is characterized by enhanced platelet generation and thrombotic complications. Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A(2) (TXA(2)) in the majority of ET patients. In the present study, we investigated the determinants of aspirin-insensitive platelet TXA(2) biosynthesis and whether it could be further suppressed by changing the aspirin dose, formulation, or dosing interval. In 41 aspirin-treated ET patients, the immature platelet count predicted serum TXB(2) independently of platelet count, age, JAK-2 V617F mutation, or cytoreduction (ß = 3.53, P = .001). Twenty-one aspirin-treated patients with serum TXB(2) ≥ 4 ng/mL at 24 hours after dosing were randomized to the following 7-day regimens in a crossover design: enteric-coated aspirin 100 mg twice daily, enteric-coated aspirin 200 mg once daily, or plain aspirin 100 mg once daily. A twice-daily regimen caused a further 88% median (IQR, 78%-92%, P < .001) TXB(2) reduction and normalized the functional platelet response to aspirin, as assessed by urinary 11-dehydro-TXB(2) excretion and the VerifyNow Aspirin assay. Doubling the aspirin dose reduced serum TXB(2) only partially by 39% median (IQR, 29%-54%, P < .05). We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1, and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose.
Subject(s)
Aspirin/therapeutic use , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/metabolism , Thromboxane A2/biosynthesis , Acceleration , Adult , Aged , Algorithms , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/administration & dosage , Cross-Over Studies , Cross-Sectional Studies/statistics & numerical data , Drug Resistance/drug effects , Female , Half-Life , Humans , Male , Metabolic Networks and Pathways/drug effects , Middle Aged , Molecular Targeted Therapy/methods , Protein Biosynthesis/drug effects , Thromboxane A2/pharmacokineticsABSTRACT
The present study aimed to investigate potential drug interactions between darunavir and raltegravir in patients treated for HIV infection. We enrolled HIV-infected subjects on darunavir-containing regimens that underwent measurement of plasma darunavir trough concentration (12±3 h after dosing). Two groups of patients were compared: those taking darunavir plus a nucleoside/nucleotide backbone (group 1) or a backbone+raltegravir (group 2). Interindividual pharmacokinetic variability was evaluated through the coefficient of variation (CV(inter)). We obtained 156 plasma samples from 63 patients, of which 44 in group 1 and 19 in group 2. Overall, darunavir geometric mean concentration was 2.90 mg/L (95% CI 2.34-3.60) while ritonavir geometric mean concentration was 0.21 mg/L (95% CI 0.17-0.27). We observed a high inter-individual variability in darunavir (CV(inter) 59%) and ritonavir (CV(inter) 103%) plasma levels. Darunavir concentration correlated with concomitant ritonavir levels (r=0.476, p<0.001). Patients in group 1 had a higher darunavir geometric mean concentration than those in group 2 [3.44 mg/L (95% CI 2.79-4.23) versus 1.95 mg/L (95% CI 1.19-3.20), p=0.017]. However, the proportion of subjects with concomitant HIV-RNA <50 copies/mL was higher in group 2 (78.9% versus 47.7%, p=0.028). In a multivariable model, raltegravir co-administration was independently related to a lower darunavir concentration (mean difference -0.25 log(10) mg/L, 95% CI -0.46/-0.04, p=0.020) after adjusting for time from last drug intake and concomitant drugs used. In conclusion, a potential drug interaction between darunavir and raltegravir was observed, although this did not seem virologically significant. For the distinct metabolic pathways of these drugs, its mechanism remains to be determined.
Subject(s)
HIV Infections/blood , Pyrrolidinones/blood , Ritonavir/blood , Sulfonamides/blood , Adult , Darunavir , Drug Interactions/physiology , Drug Therapy, Combination , Female , HIV Infections/drug therapy , Humans , Male , Middle Aged , Pyrrolidinones/administration & dosage , Raltegravir Potassium , Ritonavir/administration & dosage , Sulfonamides/administration & dosageABSTRACT
We report a case of a vertically infected woman treated with darunavir/ritonavir plus a standard backbone before pregnancy. The analysis of darunavir/ritonavir concentrations in peripheral maternal plasma throughout pregnancy, as well as in umbilical cord blood at delivery, showed low levels of darunavir in the mother and limited transfer across the placenta.
Subject(s)
Drug Resistance, Multiple, Viral , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , HIV-1/drug effects , Pregnancy Complications, Infectious/drug therapy , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Darunavir , Drug Therapy, Combination , Female , Fetal Blood/chemistry , HIV Infections/blood , HIV Infections/transmission , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/therapeutic use , HIV-1/genetics , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/virology , RNA, Viral/genetics , RNA, Viral/isolation & purification , Ritonavir/blood , Ritonavir/therapeutic use , Sulfonamides/blood , Sulfonamides/therapeutic use , Young AdultABSTRACT
OBJECTIVES: To assess the inter-individual and intra-individual plasma concentration variabilities of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in routine clinical practice and to investigate their relationships with virological failure. METHODS: We retrospectively enrolled HIV-infected patients undergoing therapeutic drug monitoring (TDM) of NNRTIs and PIs during routine outpatient visits. Plasma drug concentrations were measured by HPLC-UV and were considered therapeutic if above the proposed minimum efficacy trough concentration. Inter-individual and intra-individual variabilities were evaluated through the coefficient of variation (CV). RESULTS: A total of 457 PI and 172 NNRTI plasma concentrations were measured from 363 patients (HIV-RNA <50 copies/mL in 70.8%, median CD4 count 434 cells/mm(3)). NNRTIs showed less inter-individual (CV(inter) 54.8% versus 84.3%) and intra-individual (CV(intra) 19.0% versus 38.1%) pharmacokinetic variabilities than PIs. Intra-individual variability was constantly lower than inter-individual variability for each drug. Subtherapeutic drug concentrations were observed in 106 samples (16.9%). Older age (P = 0.020) and higher viral load (P = 0.013) were associated with subtherapeutic levels. Patients with therapeutic levels had a viral load of <50 copies/mL more frequently than those with subtherapeutic levels (74.8% versus 63.2%, P = 0.020). The estimated proportion with virological failure at 24 weeks was 0.21 in patients with suboptimal baseline drug levels and 0.08 in those with optimal levels (P < 0.001). In the multivariate analysis, therapeutic drug levels showed an independent negative association with virological failure (P = 0.004). CONCLUSIONS: A wide inter-individual and limited intra-individual pharmacokinetic variabilities, together with the demonstration of a concentration-response relationship, suggest that TDM is a useful tool for the clinical management of patients treated with NNRTIs or PIs.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/pharmacokinetics , Reverse Transcriptase Inhibitors/therapeutic use , Adult , CD4 Lymphocyte Count , Chromatography, High Pressure Liquid , Female , Humans , Male , Middle Aged , Plasma/chemistry , Retrospective Studies , Treatment Outcome , Viral LoadABSTRACT
BACKGROUND/AIMS: Transarterial chemoembolization is widely used for palliative treatment of hepatocellular carcinoma, but patient's characteristics associated with maximal benefit are still undefined. METHODOLOGY: In 81 cirrhotic patients with unresectable hepatocellular carcinoma, who underwent transarterial chemoembolization, variables correlated with survival were studied. In 46/81, the antipyrine metabolism test has been performed before and 72 hours after first transarterial chemoembolization. RESULTS: Mean overall survival of whole population was 22 months. One-, two-, and three-year survival rates were respectively 85%, 38.6%, and 18.1%. Better survival was observed in those patients who received more than one treatment (p = 0.016), while no relationship was found with treatment response, drug used, or number of lobes involved. Univariate analysis of the subgroup with antipyrine pharmacokinetic data revealed a significant relation between survival and baseline albumin (p = 0.039), total cholesterol (p = 0.036), AST (p = 0.017), log of total bilirubin (p = 0.017), and Child-Pugh class (p = 0.029), but not with parameters of antipyrine metabolism. Antipyrine metabolism was not significantly modified by transarterial chemoembolization in the subgroup tested before and after the first treatment. Using Cox regression analysis and selecting AST and log of total bilirubin, a prognostic index was defined: prognostic index 0.006 (AST-83.044) + 0.638 [log of total bilirubin-0.1175]. One-, two-, and three-year survival rates were respectively 92%, 59.2%, and 29.6% for the patient group with prognostic index < 0, and 76%, 14.3%, and 4.8% for the group with prognostic index > 0 (p < 0.01). CONCLUSIONS: Transarterial chemoembolization is a safe procedure and appears beneficial for those patients with a good functional hepatic reserve. The antipyrine metabolism test does not provide any additional prognostic information.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Carboplatin/administration & dosage , Carboplatin/therapeutic use , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Liver Cirrhosis/mortality , Liver Cirrhosis/therapy , Liver Neoplasms/mortality , Liver Neoplasms/therapy , Adult , Age Factors , Aged , Carcinoma, Hepatocellular/complications , Female , Humans , Infusions, Intra-Arterial , Liver Cirrhosis/etiology , Liver Neoplasms/complications , Male , Middle Aged , Prognosis , Recovery of Function , Survival RateABSTRACT
OBJECTIVES: In the present work, a method to induce experimental allergic encephalomyelitis (EAE) in female SJL/J mice was developed and validated in our laboratory. Although the latter is a popular animal model to mimic human multiple sclerosis, it remains to be clarified if: (1) the measurement of circulating antibodies against myelin antigens can be used as an index to predict the development of clinical EAE, as well as the severity of disease, and (2) the genetic susceptibility of this strain is associated with altered hypothalamo-pituitary-adrenal (HPA) function. METHODS AND RESULTS: We observed that SJL/J mice display a strong humoral response to immunization with myelin basic protein (MBP), as assessed by the titration of circulating anti-MBP antibodies. However, there was no apparent correlation between the presence and amount of circulating antibodies and the occurrence or severity of disease. Concerning the responsiveness of the HPA axis, we observed that circulating corticosterone levels are not modified at all during the induction of EAE, whereas an increase is observed at a later stage of the disease. CONCLUSIONS: The above profile is strongly reminiscent of the HPA axis response to the induction of EAE in Lewis rats, suggesting that the susceptibility of SJL/J mice to EAE may similarly be caused, at least in part, by blunted HPA reactivity to immune challenges.
Subject(s)
Antibody Formation/genetics , Encephalomyelitis, Autoimmune, Experimental/genetics , Genetic Predisposition to Disease/genetics , Hypothalamo-Hypophyseal System/immunology , Neuroimmunomodulation/genetics , Pituitary-Adrenal System/immunology , Animals , Antibody Formation/immunology , Autoantibodies/blood , Autoantibodies/genetics , Autoantibodies/immunology , Central Nervous System/immunology , Central Nervous System/pathology , Central Nervous System/physiopathology , Cortisone/blood , Cortisone/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/blood , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , Hypothalamo-Hypophyseal System/physiopathology , Mice , Mice, Inbred Strains , Myelin Basic Protein/immunology , Myelin Basic Protein/pharmacology , Neuroimmunomodulation/immunology , Pituitary-Adrenal System/physiopathology , Reaction Time/drug effects , Reaction Time/genetics , Reaction Time/immunologyABSTRACT
Current evidence suggests that the drug-metabolizing capacity of the liver can be altered by neoplastic lesions and by the chemotherapeutic agents used to treat them. Antipyrine metabolism is a widely used dynamic test for assessing mixed hepatic oxidase system activity in humans. This study was conducted to determine the effects of 5-fluorouracil-folinic acid chemotherapy on hepatic drug metabolization in patients with diffuse liver metastases from colorectal tumors using antipyrine metabolism as an index. Twenty-three patients, all with diffuse liver metastases from primary colorectal tumors and normal liver function tests, were treated with 5-day cycles of 5-fluorouracil (5-FU) (370 mg m(minus sign2) day(minus sign1) I.V.) and folinic acid (200 mg m(minus sign2) day(minus sign1) I.V.) administered every 28 days. Antipyrine metabolism was assessed before initiation of therapy and after each 5-day cycle to determine the effects of this chemotherapeutic protocol on the mixed-hepatic oxidase system. Response to treatment was assessed after 4 months. None of the patients displayed any change in antipyrine metabolism following treatment. There was no correlation between the ability to metabolize antipyrine and the response to chemotherapy. 5FU has been found to decrease antipyrine metabolism in rats with no liver disease. The absence of such an effect in our patients is thought to be due to inductive effects exerted by the metastases on the mixed hepatic oxidase system and modification of 5-FU metabolism by folinic acid. The liver appears to have an enormous functional reserve, even when there is massive tumor involvement.