PubMed Health⌕ Search

Biomedical subjects

K Muro

Publications and source records attributed to K Muro.

At least 19 recordsLinked to original sources
PubMed2006

Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: A combination of irinotecan with continuous intravenous infusions of 5-fluorouracil (5-FU) and leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. This phase II study evaluated the efficacy and safety of the oral fluoropyrimidine S-1 plus irinotecan in patients with previously untreated advanced or recurrent colorectal cancer. PATIENTS AND METHODS: Forty eligible patients with histologically confirmed colorectal adenocarcinoma received this treatment. S-1 was administered orally on days 1 to 14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg (BSA < 1.25 m(2)), 50 mg (BSA > or = 1.25 to < 1.50 m(2)), or 60 mg (BSA > or = 1.50 m(2)). Irinotecan (150 mg/m(2)) was administered by intravenous infusion on day 1. RESULTS: A total of 327 courses of treatment were administered to 40 patients. Five patients had complete responses, and 20 had partial responses. The overall response rate was 62.5% (95% confidential interval, 47.5%-77.5%). Median progression-free survival was 8.0 months (95% confidential interval, 5.2-11.4 months). The rates of grade 3 or 4 toxicity were as follows: neutropenia, 15%; anemia, 7.5%; anorexia, 12.5%; and diarrhea, 7.5%. CONCLUSIONS: Combined treatment with S-1 and irinotecan is an effective, well tolerated, and convenient regimen in patients with advanced colorectal cancer. Our findings suggest that combined treatment with S-1 and irinotecan is a promising regimen, offering benefits in terms of safety and survival as compared with conventional regimens in patients with advanced colorectal cancer.

Adenocarcinoma↗
PubMed2004

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin.

NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.

Aged↗
PubMed2004

Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV.

PURPOSE: To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m2/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course. RESULTS: The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve-adjusted body surface area appeared to be comparable between the two groups. CONCLUSION: The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.

Administration, Oral↗
PubMed2004

Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer.

BACKGROUND: MCC-465 is an immunoliposome-encapsulated doxorubicin (DXR). The liposome is tagged with polyethylene glycol (PEG) and the F(ab')2 fragment of human monoclonal antibody GAH, which positively reacts to >90% of cancerous stomach tissues, but negatively to all normal tissues. In preclinical studies, MCC-465 showed superior cytotoxic activity against several human stomach cancer cells compared with DXR or DXR-incorporated PEG liposomes. The main purpose of this trial was to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), recommended phase II dose and pharmacokinetics (PK) of MCC-465. PATIENTS AND METHODS: Patients with metastatic or recurrent stomach cancer were eligible for entry. The initial dose was 6.5 mg/m2. MCC-465 was administered as a 1-h infusion every 3 weeks and the treatment continued for up to six cycles. RESULTS: Twenty-three patients received a total of 62 cycles at the 6.5-45.5 mg/m2 dose level. DLTs were myelosuppression and appetite loss at the 45.5 mg/m2 dose level. Other toxicities were mild. Neither palmar-plantar erythrodysesthesia nor cardiotoxicity was observed. Acute reactions related to infusion were observed commonly in 16 patients over the entire dose range. While no antitumor response was observed, stable disease (SD) was observed in 10 out of 18 evaluable patients. The pharmacokinetic study showed a similar AUC and Cmax to Doxil. CONCLUSION: MCC-465 was well tolerated. The recommended dose for a phase II study of MCC-465, for a 3-week schedule, is considered to be 32.5 mg/m2 in an equivalent amount of DXR.

Adult↗
PubMed2004

A phase II study of single-agent docetaxel in patients with metastatic esophageal cancer.

BACKGROUND: To evaluate the activity and toxicity of docetaxel in patients with metastatic esophageal cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed carcinoma of the esophagus with measurable metastatic sites according to Response Evaluation Criteria in Solid Tumors (RECIST). Patients were either chemotherapy-naïve or previously treated with one regimen of chemotherapy. Docetaxel 70 mg/m(2) was administered intravenously over 1-2 h, every 21 days. RESULTS: Of 52 patients enrolled in this study, three were excluded because they did not receive docetaxel due to worsening condition after enrollment. Thirty-six patients had received prior platinum-based chemotherapy. The majority of patients (94%) had squamous cell carcinoma. Ten of 49 evaluable patients [20%; 95% confidence interval (CI) 10-34%] showed a partial response. Of the 10 partial responses, six patients had received prior platinum-based chemotherapy. Grade 3 or 4 neutropenia was noted in 43 of 49 patients (88%), and nine of 49 patients (18%) developed febrile neutropenia. Twenty-eight of 49 patients (57%) required lenograstim. Grade 3 anorexia and fatigue occurred in nine (18%) and six (12%) patients, respectively. Median survival time was 8.1 months (95% CI 6.6-11.3) and the 1-year survival rate was 35% (95% CI 21-48%). CONCLUSIONS: Docetaxel as a single agent is effective in esophageal cancer, but careful management of neutropenia is needed.

Adenocarcinoma↗
PubMed2003

Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil.

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg m(-2) day(-1) for 5 days. After a washout period of 9 days, the patients received two divided doses daily for 28 days. S-1 was administered orally at about 0900 and 1900 hours. The daily dose of S-1 in terms of tegafur was 80 mg day(-1) in patients with a body surface area (BSA) of <1.25 m(2), 100 mg day(-1) in those with a BSA of >or=1.25 m(2) to <1.5 m(2), and 120 mg day(-1) in those with a BSA of >or=1.5 m(2). Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition (pharmacodynamic analysis) in the same patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC(0-10 h)) of 5-FU on day 5 was 728+/-113 ng h ml(-1) for PVI of 5-FU and 1364+/-374 ng h ml(-1) for S-1. The median 5-FU PVI : S-1 ratio of the AUC(0-10 h) of 5-FU was 1.9. The AUC(0-10 h) of FBAL on day 5 of PVI of 5-FU was 9465+/-3225 ng h ml(-1), AUC(0-10 h), as compared with 1725+/-605 ng h ml(-1) on day 5 of S-1 treatment. The AUC(0-10 h) of uracil on day 5 was 252+/-60 ng h ml(-1) with PVI of 5-FU and 12 582+/-3060 ng h ml(-1) with S-1. The AUC(0-10 h) of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.

Administration, Oral↗
PubMed2001

Inflammatory endobronchial stenosis.

We encountered a 71-year-old woman with inoperable bronchial stenosis of the right main bronchus, which was caused by inflammatory granulation infected with Pseudomonas aeruginosa in posttuberculous bronchiectasis. Two months after placement of self-expanding nitinol stents, fiberoptic bronchoscopic examination to investigate hemosputum revealed endobronchial granuloma formation. Endobronchial granulation has disappeared with long-term oral administration of tranilast.

Administration, Oral↗
PubMed2001

Phase I-II study of irinotecan combined with mitomycin-C in patients with advanced gastric cancer.

BACKGROUND: Irinotecan (CPT-11) shows synergism with mitomycin-C (MMC) in a preclinical setting. The goals of this study were to determine the maximum tolerated dose (MTD), the dose limiting toxicity, the recommended dose (RD), and preliminary anti-tumor activity in a combined CPT-11 and MMC treatment of advanced gastric cancer. PATIENTS AND METHODS: The study was designed to evaluate escalated doses of CPT-11 and MMC administered every two weeks. Five escalating dose levels were studied (CPT-11/ MMC: 100/5; 125/5; 150/5; 150/7; 150/10 mg/m2). RESULTS: Thirty-one patients were enrolled. Thirty patients were assessable for toxicity and tumor response for 89 treatment cycles. The median age was 60 years (32-73 years), and most patients (90%) had a performance status of 0 to 1. Fourteen patients were previously treated and 17 were chemotherapynaive. The MTD was CPT-11 150 mg/m2 plus MMC 10 mg/m2, in which all three patients experienced grade 4 neutropenia. including one episode of prolonged and one of febrile neutropenia, and one patient experienced grade 3 diarrhea during the first cycle. Fifteen partial responses were observed. CONCLUSIONS: The RD based on this phase I-II study was CPT-11 150 mg/m2 plus MMC 5 mg/m2 administered every two weeks. This combination demonstrates promising activity against advanced gastric cancer and warrants further investigation in another phase II study.

Adult↗
PubMed2001

Specific T-cell receptor usage with cytokinemia in Henoch-Schönlein purpura nephritis associated with Staphylococcus aureus infection.

OBJECTIVES: We sought to evaluate the mechanism of Henoch-Schönlein purpura nephritis (HSPN) associated with Staphylococcus aureus (S. aureus) infection. DESIGN: We evaluated six male patients with HSPN associated with S. aureus infection. Routine laboratory examinations, bacteriological examination, histological examination, and analysis of serum cytokine levels were performed in all cases. In addition, peripheral blood mononuclear cells (PBMC) obtained from the six patients and 45 normal individuals were stained with labelled-monoclonal antibodies against six variable parts of the beta-chain (Vbeta) of the T-cell receptor (TCR), and stained cells were analysed by flow cytometry. RESULTS: Patients with HSPN associated with S. aureus infection showed features of the nephrotic syndrome with rapidly progressive glomerulonephritis, as well as varying degrees of mesangial proliferative glomerulonephritis with crescent formation. Serological examination showed elevated levels of serum IgA and IgG as well as immune complexes after the onset of infection. The percentage of Vbeta-(5.2 + 5.3) and Vbeta 8-positive cells in patients with HSPN were significantly higher than in normal individuals; moreover, specific TCR-Vbeta usage was not observed in patients with HSPN whose S. aureus infection had improved. Serum levels of IL-1beta, IL-2, IL-6, IL-8 and TNF-alpha in patients with HSPN were significantly higher than in normal individuals, and normalized at the healing stage of S. aureus infection. CONCLUSION: Conventional antigens and/or staphylococcal enterotoxins originated from S. aureus might have been involved in the pathogenesis of HSPN in the present cohort. Therefore, steroid or other immunosuppressive therapies could not be utilized despite the high activity of glomerulonephritis, and as a result the prognoses of these cases of HSPN were serious.

Adult↗
PubMed2001

Complete response achieved following administration of S-1 in a patient with adrenal gland metastasis of 5-FU-resistant gastric cancer: a case report.

A 62-year -old male patient who had undergone total extirpation of type 3 cancer of the greater curvature of the upper stomach body at another hospital received postoperative chemotherapy with 5-FU and methotrexate. The patient was subsequently treated with oral 5-FU. About 1 year later, a 4 cm tumor of the left adrenal gland was revealed by abdominal CT and diagnosed as gastric cancer metastasizing to the adrenal gland. The patient was referred to our hospital for close examination and treatment and admitted. After his informed consent had been obtained, the patient received one course (4-week administration and 2-week withdrawal) of S-1 at 50 mg/body x 2/day. Abdominal computed tomography performed after the end of the one course revealed that the tumor had become undetectable. This condition was still maintained at the end of two courses and judged to be complete response (CR) (in accordance with the WHO Efficacy Judgment Criteria). CR has continued to be maintained to the present time, even after seven courses. There has been no previous report of S-1 showing remarkable effectiveness in a patient with 5-FU-resistant gastric cancer metastasizing to the adrenal gland. We consider that the efficacy of S-1 for treatment of 5-FU-resistant gastric cancer should be verified.

Adrenal Gland Neoplasms↗
PubMed2001

Th2 predominance at the single-cell level in patients with IgA nephropathy.

BACKGROUND: Abnormalities of lymphocyte function have been reported to be involved in the pathogenesis of IgA nephropathy (IgA-N). The aim of this study was to investigate helper T (Th) predominance at the single-cell level, one of the abnormalities of lymphocyte function in IgA-N. METHODS: Using flowcytometry, we assessed the levels of circulating Th cells in IgA-N patients (n=30), and in normal individuals (n=30) based on the expression of intracellular Th1 cytokines for interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), and of intracellular Th2 cytokines for IL-4, IL-10, and IL-13. Because the production of each cytokine had a specific time course, we examined cytokine synthesis at 3, 6, 9, and 12 h after stimulation. RESULTS: The percentages of IL-2-positive Th cells from IgA-N patients were significantly lower than in normal individuals at 6, 9, and 12 h, with the difference becoming greater with time. The number of IFN-gamma-positive Th cells in IgA-N patients was significantly lower than in normal individuals at 9 h, and the number of IFN-gamma-positive Th cells increased more at 12 h than at 3 h in both groups. IL-4 and IL-13 expression was increased in patients with IgA-N at 6 h compared with normal individuals. In IgA-N patients, the percentage of IL-10-positive Th cells was significantly higher than that in normal individuals at each time-point. CONCLUSION: A polarization toward Th2 response at the stimulated lymphocyte level may lead to immune abnormalities in IgA-N.

Adult↗
PubMed2001

Heterogeneity of prognosis in adult IgA nephropathy, especially with mild proteinuria or mild histological features.

OBJECTIVE: The present study was undertaken to clarify the clinical course and prognosis of adult patients with primary IgA nephropathy (IgAN), especially with mild proteinuria or mild histological alternations. PATIENTS AND METHODS: A population of 735 IgAN patients whom we were able to observe for more than two years was examined. RESULTS: A total of 115 patients (15.6%) was on dialysis during the observation period. The overall 5-year renal survival rate was 92.0%. On the other hand, 166 patients (22.6%) were in clinical remission. A group with mild proteinuria included 197 patients (26.8%). Forty-seven patients of this group showed minor glomerular abnormalities, whereas 12 patients with mild proteinuria showed severe mesangial involvement. Three patients with mild proteinuria were on dialysis during the observation period, whose proteinuria was increased during the clinical course. A group with minor glomerular abnormalities included 82 patients (11.2%). Forty-seven patients of this group showed mild proteinuria, of whom 12 patients showed moderate proteinuria. However, three patients with minor glomerular abnormalities who were not on dialysis showed loss of renal function. CONCLUSION: These results indicated the heterogeneity of the course and prognosis in IgAN. Even if a patient's initial clinical or histological findings are comparatively mild, strict follow-up management is needed.

Adolescent↗
PubMed2000

Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.

Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.

Adult↗
PubMed2000

Evaluation of tracheo-bronchial wall invasion using transbronchial ultrasonography (TBUS).

BACKGROUND: Whereas accurate evaluation of tumor invasion into the tracheo-bronchial wall is a critical factor in decision-making of therapy for intra-thoracic malignancies, it is sometimes difficult with usual thoracic imaging techniques such as computed tomography. As recent progress in technology of ultrasonography is marked, usefulness of transbronchial ultrasonography (TBUS) in evaluation of tracheo-bronchial wall invasion was assessed. METHODS: Following routine fiberoptic bronchoscopy, an ultrasound probe (20 MHz) covered with a balloon sheath was inserted through the bronchoscope. After air present between the ultrasound probe and the tracheo-bronchial wall was eliminated with filling the balloon with distilled water, TBUS imaging was taken. RESULTS: With TBUS, normal tracheo-bronchial wall was represented as a five-layer structure at the cartilagenous portion and a three-layer structure at the membranous portion. Based on this normal TBUS imaging, tumor extent was judged in 35 patients with intra-thoracic malignancies. Among 25 patients with extra-wall tumor including esophageal cancer (n=15) and metastatic lymph nodes (n=7), tracheo-bronchial wall invasion was clearly demonstrated in nine patients, and no invasion was demonstrated in the other 16 patients. Among ten patients with tumor originating from the tracheo-bronchial wall, tumor extent beyond outer border of the wall was demonstrated with TBUS in five patients. These diagnoses were examined pathologically in 15 patients who underwent the operation, and the accuracy was 93.3%. CONCLUSIONS: It is suggested TBUS can be a useful diagnostic tool in evaluation of tumor invasion to the tracheo-bronchial wall.

Adult↗
PubMed2000

Cytokines and T-cell responses in superantigen-related glomerulonephritis following methicillin-resistant Staphylococcus aureus infection.

BACKGROUND: We have previously reported that 10 patients who developed glomerulonephritis (GN) in association with methicillin-resistant Staphylococcus aureus (MRSA) infection showed a marked increase in DR+CD4+ and DR+CD8+ subsets of T cells and in T cells expressing several T-cell receptor (TCR) V beta+cells, perhaps representing V beta-specific T-cell activation by MRSA-derived superantigens (Kidney Int 1995; 47: 207-216). In this study we examine cytokine levels, T-lymphocyte subsets, natural killer NK cells, memory T cells, and the expression of IL-2 receptors in order to better understand the role of bacterial superantigens and cytokines in the pathogenesis of MRSA-associated GN. METHODS: Twenty-two patients with MRSA infection who later developed GN caused by staphylococcal enterotoxin were evaluated immunologically in comparison with patients whose MRSA infection was not followed by GN (non-GN group) and normal individuals. RESULTS: Among peripheral lymphocytes, the frequency of T cells expressing several TCR V betas, especially V beta 5-family TCR, was higher in the GN group than in both the non-GN group and the normal healthy control group. GN patients also showed increased serum levels of several cytokines, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-2, IL-6, IL-8, and IL-10, which have been implicated in the onset of nephritis. Memory cells, and IL-2 receptors also were elevated in the GN group. CONCLUSION: These results suggest that T cells activated by MRSA-derived staphylococcal enterotoxins and subsequent production of cytokines may play an important role in the pathogenesis of MRSA-associated GN.

Adult↗
PubMed2000

Prediction of in vivo drug-drug interactions based on mechanism-based inhibition from in vitro data: inhibition of 5-fluorouracil metabolism by (E)-5-(2-Bromovinyl)uracil.

The fatal drug-drug interaction between sorivudine, an antiviral drug, and 5-fluorouracil (5-FU) has been shown to be caused by a mechanism-based inhibition. In this interaction, sorivudine is converted by gut flora to (E)-5-(2-bromovinyl)uracil (BVU), which is metabolically activated by dihydropyrimidine dehydrogenase (DPD), and the activated BVU irreversibly binds to DPD itself, thereby inactivating it. In an attempt to predict this interaction in vivo from in vitro data, inhibition of 5-FU metabolism by BVU was investigated by using rat and human hepatic cytosol and human recombinant DPD. Whichever enzyme was used, increased inhibition was observed that depended on the preincubation time of BVU and enzyme in the presence of NADPH and BVU concentration. The kinetic parameters obtained for inactivation represented by k(inact) and K'(app) were 2.05 +/- 1.52 min(-1), 69.2 +/- 60.8 microM (rat hepatic cytosol), 2.39 +/- 0.13 min(-1), 48.6 +/- 11.8 microM (human hepatic cytosol), and 0.574 +/- 0.121 min(-1), 2.20 +/- 0.57 microM (human recombinant DPD). The drug-drug interaction in vivo was predicted quantitatively based on a physiologically based pharmacokinetic model, using pharmacokinetic parameters obtained from the literature and kinetic parameters for the enzyme inactivation obtained in the in vitro studies. In rats, DPD was predicted to be completely inactivated by administration of BVU and the area under the curve of 5-FU was predicted to increase 11-fold, which agreed well with the reported data. In humans, a 5-fold increase in the area under the curve of 5-FU was predicted after administration of sorivudine, 150 mg/day for 5 days. Mechanism-based inhibition of drug metabolism is supposed to be very dangerous. We propose that such in vitro studies should be carried out during the drug-developing phase so that in vivo drug-drug interactions can be predicted.

Adult↗