Urinary beta 2-microglobulin as an indicator for impaired excretion of methotrexate

Twenty cases treated with high-dose methotrexate (MTX) infusions were studied to determine whether urinary beta 2-Microglobulin (beta 2-M) is a reliable indicator to predict impaired excretion of methotrexate. Before and after MTX infusions, the levels of urinary beta 2-M were measured along with serum creatinine, uric nitrogen, and creatinine clearance. MTX clearance was found to be impaired in four of the 20 infusions, although concentrations of serum creatinine and uric nitrogen, and creatinine clearance were normal prior to the infusions. In the four cases that resulted in impaired excretion, a significant increase of beta 2-M levels was noted before and after the high-dose MTX infusion (p less than 0.01). Although one of the four cases showed a normal level of beta 2-M before the infusion, the post-infusion level of beta 2-M extremely high. This raised level of beta 2-M was thought to be caused by impaired excretion due to decreased amounts of urine. We conclude that urinary beta 2-M is a sensitive indicator of impaired excretion of high-dose MTX infusion, and especially when levels of more than 250 ng/ml of urinary beta 2-M are found to exist, it seems to difficult to clear the drug following high-dose MTX treatment.     

Enhancement of methotrexate nephrotoxicity after cisplatin therapy

We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate-induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate-induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined-drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.     

Comparison of methods for evaluating the nephrotoxicity of cisplatin

The BUN, serum creatinine, creatinine clearance and the urinary excretion of leucine aminopeptidase (LAP), alkaline phosphatase (ALP), beta 2-microglobulin (beta-m), and N-acetyl-beta-glucosaminidase (NAG), were measured in 21 gynecological cancer patients treated with CAPF (CPA + ADM + CDDP + 5-FU) to evaluate the sensitivity of these indices to renal tubular damage. After receiving CDDP almost all patients displayed an increase in excretion of beta-m but no urinary enzyme activities. However, NAG index (NAG activity/urinary creatinine) rose markedly in all patients. We concluded that NAG index is a valuable method in providing sensitive indices for detecting renal tubular damage caused by CDDP.     

Assessment of renal function during high-dose cis-platinum therapy in patients with ovarian carcinoma

Summary Five courses of cis-dichlorodiammine platinum (II) (100 mg/m²) were given to 22 patients with advanced stage III and IV ovarian cancer. Renal function was assessed by measurement of creatinine clearance, urinary osmolality and urinary B₂-microglobulin (B₂MG) in all patients, and by urinary alanine aminopeptidase (AAP) and N-acetyl-B-glucosaminidase (NAG) excretion in seven patients.Serum creatinine, creatinine clearance, urinary osmolality, and urinary B₂-microglobulin were within the reference ranges and did not change significantly after five courses of cis-platinum in any patient.There was a significant increase in the urinary excretion of both enzymes (AAP and NAG) within 2 days of cis-platinum administration (NAG P<0.05 and AAP P<0.07). There was evidence of a cumulative effect during treatment for AAP (P<0.025).     

High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL)

PURPOSE: The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination. PATIENTS AND METHODS: The majority of the 264 children were being treated for ALL. According to the NOPHO-92 protocol, 5 or 8 g MTX/m(2) was administered over 24 h. Serum creatinine was assessed daily. In 11 patients from one centre, renal function was studied in more detail using serum cystatin C, iohexol clearance, and urinary albumin, IgG and protein HC. RESULTS: Increased serum creatinine correlated significantly with the elimination time of MTX, whereas no indications were found of tubular or barrier function damage. Of the 1164 courses, 44 had delayed elimination of MTX (>/=120 h). Serum MTX >150 microM at the end of infusion had a sensitivity of 0.27 and a specificity of 0.94 to predict delayed MTX elimination, and >/=50% increase in serum creatinine during the first treatment day (creatinine ratio) had a sensitivity of 0.32 and a specificity of 0.99. The corresponding risk ratios were 5 and 19 for MTX >150 micro M and creatinine ratio, respectively. In courses with a normal elimination time (<72 h), 99% of the courses had a rise in serum creatinine of less than 50%. CONCLUSIONS: Elevation of serum creatinine by more than 50% is a better predictor of delayed elimination than the level of serum MTX at the end of MTX infusion, especially if information on previous creatinine measurements is used to reduce the impact of an occasionally low serum creatinine value before the start of the MTX infusion.     

Diuretic response to cyclophosphamide in rats bearing a matrix metalloproteinase-9-producing tumour.

When cyclophosphamide (CY) (100-120 mg kg(-1)) was administered intravenously (i.v.) to normal F-344 rats, oliguria occurred over the 5-day observation period. Conversely, in rats bearing matrix metalloproteinase-9 (MMP-9) producing 13762NF mammary adenocarcinoma (MTLn3 clone), polyuria occurred chiefly during the first 24 h after CY treatment. In parallel with urine volume, a decrease in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) was observed during the first 5 days after CY treatment in normal rats, but it increased in MTLn3-bearing rats. No elevation in blood urea nitrogen (BUN) or serum creatinine (Cr) values was observed for either group. Both urine volume and urinary excretion of NAG after CY treatment were lower in rats bearing the MTC clone (lower production of MMP-9) than for those bearing the MTLn3 clone. In the case of treatment with cisplatin (CDDP, 4-6 mg kg(-1)), urine volume, urinary NAG excretion and BUN and serum Cr values all increased in normal rats and were all found to be higher in MTLn3-bearing rats than in normal rats. The diuretic response to these drugs in tumour-bearing (TB) rats may be associated with MMP-9 produced by the tumour cells. This report suggests that the nephrotoxicity due to anti-cancer drugs may change when the drugs are used for the treatment of patients bearing a MMP-9-producing tumour.     

The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate

The pharmacokinetics of high-dose methotrexate (MTX, 5-15 g/m2) were evaluated in 11 children and adolescents who had previously received two to eight doses of cisplatin (90 mg/m2) in the treatment of malignant solid tumors. The half-life for disappearance of MTX from serum during the first 24 hours after infusion was determined from serum samples obtained at the end of a six-hour infusion and six, 12, and 24 hours after infusion. These values were compared to a mean half-life of 2.83 (+/- 0.34) hours following 489 courses administered to 71 patients who had not received cisplatin. Stepwise multiple linear regression analysis of patient variables revealed cumulative cisplatin dosage and time from last cisplatin dose as the best predictors of MTX half-life (r2 = 65.4%, p less than 0.001). The best predictors of 24-hour serum concentration were cumulative cisplatin dosage and MTX dosage (r2 = 54.2%, p less than 0.001) in the multiple linear regression model. Patients with delayed MTX clearance received additional leucovorin and experienced no severe toxicity. Patients receiving up to 270 mg/m2 of cisplatin appear to have minimal increases in MTX half-life, while the likelihood of delayed clearance increases in patients who have received 360 mg/m2 or more of cisplatin. All patients who have previously received cisplatin should be treated cautiously with high-dose MTX and prospective pharmacokinetic monitoring should be routinely performed.     

Cisplatin-induced alterations of serotonin metabolism in patients with or without emesis following chemotherapy

Serotonin (5-HT)(3) receptor antagonists are very effective in the control of cisplatin induced emesis. Nevertheless, a significant proportion of patients still experience emesis despite the use of these antiemetics. The aim of this study was to evaluate if cisplatin treated patients who vomit differ from patients who are completely protected from emesis with respect to measurable alterations of serotonin metabolism. We measured the urinary excretion of 5-hydroxyindole-acetic-acid (5-HIAA), the main metabolite of serotonin, in 24 patients with 42 courses of cisplatin containing chemotherapies. Patterns of 5-HIAA excretion were compared between patients with emesis and patients who are completely protected from vomiting. Three groups of patients without chemotherapy served as control. The first group did not receive any medication. The second and third group were given a single dose of ondansetron or metoclopramide. The median 5-HIAA/creatinine ratios in the control group ranged from 3.8 to 6.9 with a median of 6.2 (mu g 5-HIAA/mg creatinine). Neither ondansetron nor metoclopramide given without chemotherapy induced significant changes in 5-HIAA excretion patterns. 23 courses (55%) were associated with acute cisplatin-induced emesis. The median interval from the start of the cisplatin infusion to the peak 5-HIAA excretion was shorter in patients with acute emesis, but the cumulative amount of urinary 5-HIAA did not differ between patients with or without emesis. Patients who are efficiently protected from vomiting as well as patients who experience emesis show a comparable increase in urinary 5-HIAA following cisplatin therapy. The present study failed to show elevated 5-HIAA excretion levels occurring later than 24 hours following cisplatin administration. Nevertheless, patients experienced cisplatin-induced delayed emesis. Further studies are warranted to identify the pathomechanisms responsible for delayed emesis as well as that proportion of acute emesis which is refractory to 5-HT3 antagonism.     

Tubular nephrotoxicity during long-term ifosfamide and mesna therapy

Summary The nephrotoxic effects of ifosfamide were assessed in 18 children and adolescents given cumulative doses of 32–112 g/m² (1.6 g/m² per day in sequential 5-day courses) with the uroprotectant mesna (1.2 g/m² per day). Tubular nephrotoxicity was evaluated by measuring the urinary concentrations ofN-acetyl--d-glucosaminidase (NAG), alanine aminopeptidase (AAP), and total protein before and during sequential courses of therapy. Of 15 patients who had normal levels of tubular markers before ifosfamide therapy, only 1 developed a persistent increase in baseline values of the three tubular markers with the sixth course of ifosfamide. Although transient increases in the excretion of these markers were observed during each 5-day course of ifosfamide, the magnitude did not increase over sequential courses in these 15 patients. Of the remaining three patients who had increased NAG levels before ifosfamide therapy, two showed a progressive increase in enzymuria and proteinuria, and serum creatinine concentrations increased in a single patient who had obstructive uropathy. Our data suggest that children with normal renal function can be given large cumulative amounts of ifosfamide in fractionated doses with little risk of progressive clinical nephrotoxicity.Supported by Childhood Solid Tumor Program Projekt grant P01 CA 23099, Cancer Center Support (Core) grant CA-21765, and the American Lebanese Syrian Associated Charities (ALSAC)     

The long-term effect of cisplatin on renal function

The long-term effect of cisplatin on renal function was studied in a follow-up investigation, 16 to 52 months after chemotherapy in 22 patients with disseminated nonseminomatous testicular cancer. The median cumulated cisplatin dose was 452 mg/m2 (range, 275-650 mg/m2). Prehydration with isotonic saline secured diuresis above 100 ml/hour. GFR (glomerular filtration rate: 51Cr-EDTA clearance) fell by 12.5% (median, P less than 0.01) compared with the pretreatment level. Effective renal plasma flow (125I-hippuran clearance) was estimated to be likewise reduced. The serum creatinine level rose 8 mumol/1 (median, P less than 0.05) during the treatment period with no further rise afterwards. Serum magnesium and urinary excretion of beta-2-microglobulin were normal. The results indicate a moderate and permanent reduction in GFR with no signs of long-term tubular defects in patients treated with cisplatin.     

Combination effects of cis-dichlorodiammineplatinum (II) and sodium thiosulfate on renal dysfunction

Forty-five patients with lung carcinoma were randomized to receive CDDP alone (STS (-) group) or combination of sodium thiosulfate (STS (+) group). Among the 45 patients, 42 had primary lung carcinoma and four had metastatic lung carcinoma. The combination of CDDP and STS infusion was performed in twenty-three patients and CDDP alone in 22 patients. The patients given STS were evaluated for renal function and pharmacokinetics. Urinary excretion of beta 2 microglobulin (BMG) and urinary concentration of N-acetyl-beta-D-glucosaminide (NAG), which reflect the function of the proximal tubules, were almost normal in the STS (+) group, but abnormally high in the STS (-) group. For serum BMG, BUN, creatinine, and 24-h creatinine clearance, which reflect glomerular function, no significant differences were found between the two groups. Urinary platinum excretion over 24 h was 29% in the STS (+) group and 21% in the STS (-) group. Total concentration of serum platinum after 24-h administration of CDDP was 2.1 micrograms/ml in the STS (+) group and 2.4 micrograms/ml in the STS (-) group. This study indicated that the combination of CDDP and STS promotes urinary excretion of CDDP, and rescues the dysfunction of the proximal tubules.     

Clinical value of the creatinine clearance before the administration of chemotherapy with cisplatin

The creatinine clearance was calculated in standard fashion from a timed urine specimen (measured creatinine clearance [MCC]) and from a previously published formula (estimated creatinine clearance [ECC]), in 55 instances, in 19 consecutive patients who were admitted to the hospital for treatment with cisplatin. Using creatinine excretion as an index of completeness of urine collection, there were 19 (35%) inaccurate collections. The correlation between creatinine clearances calculated by both methods was excellent (r = 0.684, P less than .001) and improved when inaccurate collections were excluded (r = 0.922, P less than 0.001). A discrepancy between the two methods of 25% or more was found in 19 collections. Using data from patients with two or more collections to test whether or not the two methods produced equally variable results, indicated that the MCC is a more variable, less reliable method than the ECC. In eight of 55 urine collections, the results of MCC were not used as a guide to chemotherapy and, in an additional 16 should have not been used because of inaccuracy in the urine collection. These results suggest that the creatinine clearance as calculated by an alternative method (ECC) should replace the use of MCC when assessment of the renal function is needed before the administration of nephrotoxic agents.     

Urinary cancer-related protein EDC1 and serum inter-alpha trypsin inhibitor in breast cancer

In 1976 we isolated a novel glycoprotein labeled EDC1, Mr 27,500, which is immunologically related to the normal plasma protein inter-alpha trypsin inhibitor (IATI, Mr 160,000) and which is the major component of cancer-associated proteinuria. Urinary excretion of EDC1 (mg/g creatinine) may be classified in four ranges: i) low (less than 15); ii) light (15-30); iii) intermediate (31-45); and iv) heavy (greater than 45). Normal healthy women excrete 8.0 +/- 2.2 mg/g creatinine (average +/- SEM), whereas patients with metastatic breast cancer excrete 98.2 +/- 11.6 mg/g creatinine. Patients with a variety of non-malignant disorders excreted 14.6 +/- 4 mg EDC1/g creatinine, but patients with renal failure, rheumatoid arthritis, and infectious diseases averaged 130.3 +/- 60. Sixty-five to 95 percent of urinary immunoreactive EDC1 in the latter group was of higher molecular weight, perhaps reflecting increased renal clearance of plasma IATI. In patients undergoing excisional biopsy of breast lesions, preoperative EDC1 excretion was 21.5 +/- 3.4 in those whose lesions were benign and 43.1 +/- 7.6 in those whose lesions were malignant. Eight of these latter patients were heavy excretors; EDC1 excretion fell postoperatively in these patients. In normal serum the immunoreactive IATI (IR-IATI) exists in three molecular weight forms 160,000, 120,000 and 58,000. In patients who were heavy excretors of EDC1, the IR-IATI corresponding to Mr 58,000 was absent and total serum IR-IATI was about two-thirds of normal. There was also a negative correlation between serum levels of IATI and urinary EDC1 in these patients. These data suggest that urinary EDC1 may arise as a result of interaction between IATI and tumor-associated proteases.     

Effects of urinastatin against nephrotoxicity of cisplatinum

Nephrotoxicity is the major side effect of cisplatinum (CDDP) and it is often the dose limiting factor. We have studied the effect of urinastatin (US) to decrease the nephrotoxicity of CDDP administration. 28 patients with gynecological cancer treated by chemotherapy including CDDP (13 mg/m2 daily for 5 days) were assigned to two groups, the group with US (n = 14) and the group without US (n = 14). The former was added each 150,000 units of US before and after administration of CDDP. The BUN, serum creatinine (Cre), creatinine clearance (Ccr) and the excretion of beta 2-microglobulin (beta 2-MG) index and N-acetyl-beta-glucosaminidase(NAG)index were measured. The BUN, Cre and Ccr were within normal range during four cycles. However NAG index rose remarkably when CDDP was treated by CDDP. And the increase in NAG index, which reflect the magnitude of renal tubal damage, was less in the group with US than in the group without US. It was suggested that US had effects to reduce nephrotoxicity of CDDP in chemotherapy, and that we could treat patients by high dose CDDP.     

Intima-media thickness,myocardial perfusion and laboratory risk factors of atherosclerosis in patients with breast cancer treated with anthracycline-based chemotherapy

An increased incidence of complications of atherosclerosis has been noted in cancer survivors. The aim of the present study was to evaluate, in patients with breast carcinoma, the effect of antracycline-based chemotherapy on carotid intima-media thickness (IMT), myocardial perfusion, assessed by single-photon emission tomography (SPECT) and laboratory parameters associated with the risk of atherosclerosis. Thirty-six patients with breast cancer were evaluated before and after anthracycline-based chemotherapy. Retinol, alpha-tocopherol, glycosylated hemoglobin and urinary neopterin were measured by high-performance liquid chromatography. Peripheral blood cell count, D-dimers, fibrinogen, antithrombin, glucose, magnesium, creatinine, uric acid, albumin, C-reactive protein, lipoprotein (a), cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, homocysteine, urinary albumin and N-acetyl-beta-d-glucosaminidase (NAG) were determined with routine methods. No significant differences were observed between patients and 16 controls. Compared to the measurement before the start of therapy, peripheral blood leukocyte and platelet count, hemoglobin, creatinine, HDL cholesterol, retinol, albumin, urinary albumin and NAG decreased, and total cholesterol, LDL cholesterol, triglycerides, neopterin and mean IMT increased significantly after the treatment. Of the 36 patients who had SPECT after treatment, perfusion defects were noted only in two cases, including the patient who had perfusion defects at baseline examination and a patient who did not have a baseline SPECT. In conclusion, a significant increase in carotid IMT, total cholesterol, LDL cholesterol, triglycerides and urinary neopterin and a decrease of peripheral blood leukocyte and platelet counts, hemoglobin, creatinine, HDL cholesterol, retinol, albumin and NAG were observed after the treatment.     

Reduced ability to clear ultrafilterable platinum with repeated courses of cisplatin

Ultrafilterable plasma and urinary levels of platinum were quantitated for 24 hours after the first- and fourth-course infusion of cisplatin (CDDP) to seven patients. Four patients received 80 mg/m2 and three patients received 100 mg/m2 CDDP as a 2-hour infusion. The area under the curve (AUC) of ultrafilterable platinum, average renal clearance (CIR) of ultrafilterable platinum, and percentage of the platinum dose excreted in urine (% E) were determined for each infusion over the 26-hour period of the study. The AUC was higher in all patients after the fourth-course infusion, with a median increase of 74%. The median CLR was 494 mL/min (range, 214 to 996 mL/min) for the first course and decreased to 156 mL/min (range, 108 to 271 mL/min) for the fourth-course infusion (P less than .02). The median % E was 29.2% (range, 19.6% to 37.7%) for the first course and decreased to 19.9% (range, 12.4% to 25.9%) for the fourth-course infusion (P less than .02). There was no difference in creatinine clearance for the two infusions (median, 94 mL/min; P greater than .05). Urinary excretion of B2-microglobulin (B2-MG) and N-acetyl-B-glucosaminidase (NAG) was highly variable between patients and did not provide a useful predictor of changes in renal function. Four courses of CDDP therapy resulted in significantly reduced renal elimination of platinum in patients, probably through a reduction in the secretion of the drug in the proximal tubule of the kidney. The results suggest that increased antitumor effect and toxicity could occur in patients receiving sequential courses of cisplatin.     

Biochemical and pharmacological consequences of the interaction between methotrexate and ketoprofen in the rabbit

Severe methotrexate (MTX) toxicity is a proven complication of associations of MTX and non-steroidal anti-inflammatory drugs (NSAIDs). This study investigated the interaction between MTX (50 or 100 mg kg-1) and ketoprofen (KP) (3 mg kg-1 day-1, pretreatment for 8 days) in the rabbit. The drug association induced a reversible increase in blood urea and creatinine. The severity degree of renal dysfunction was significantly related to the MTX dose; it was not modified by prolonged exposure to KP after MTX administration. The biological markers of haematopoietic and hepatic functions were unchanged. Pretreatment by KP induced a marked reduction (70%) in the urinary excretion of the prostaglandin 6-keto-PGF1 alpha. MTX dose-related alterations in MTX pharmacokinetics were also observed with the drug association: at a MTX dose of 100 mg kg-1, the presence of KP significantly reduced the total body clearance, the renal clearance and the fraction of MTX eliminated in urine as compared to controls. An appreciable reduction in the plasma binding of MTX was also noted in vivo when KP was associated. This experimental study confirms the existence of an interaction between MTX and KP and demonstrates its renal origin.     

Renal tubular dysfunction and urinary zinc excretion in breast cancer patients treated with anthracycline-based combination chemotherapy

The survival of breast cancer patients has significantly improved through the treatment with anthracyclines. Although anthracyclines are known to produce renal disease in experimental animals, little is known about the toxicity of anthracyclines at clinically relevant doses in humans. In a previous study on cancer patients we have observed an increase in the urinary activity of N-acetyl-beta-D-glucosaminidase (NAG), an indicator of renal tubular cell dysfunction that was accompanied by increased urinary zinc loss. Because an increase in NAG activity was reported after the treatment with anthracyclines, we hypothesized that an increase in urinary NAG activity in breast cancer patients treated with anthracycline-based regimens will be accompanied by hyperzincuria and hypozincemia. Urinary and serum zinc, urinary NAG and serum creatinine were examined during chemotherapy in 26 breast cancer patients treated with anthracycline-based chemotherapy. A trend for increased NAG activity, as compared to baseline, was observed throughout the first 4 cycles of treatment. NAG activity was significantly elevated compared to pretreatment levels one week after the first, third and fourth dose of chemotherapy. Serum creatinine concentrations decreased significantly after the second cycle of therapy. On the other hand, urinary and serum zinc levels did not change significantly during the treatment. In conclusion, our data confirm the presence of mild renal tubular cell dysfunction in breast cancer patients treated with doxorubicin-based chemotherapy. Increased urinary NAG is accompanied by a decrease in serum creatinine which is consistent with hyperfiltration. These changes are not associated with abnormalities of renal zinc handling or a decrease in serum zinc concentrations.     

Enzymuria following amphotericin B application in the rat

The effect of amphotericin B application on urinary renal tubule enzyme excretion was investigated in rats treated with amphotericin B (1.5 mg kg-1 b.i.d., i.v.) for 4 days. Application of amphotericin B induced a significant higher daily urinary enzyme activity of the renal tubular enzymes N-acetyl-beta-glucosaminidase (NAG), beta-glucuronidase (GRS), alanine-aminopeptidase (AAP) and gamma-glutamyltransferase (GGT) in comparison with controls and sodium deoxycholate treated animals as well. A significant increase in the renal excretion of NAG, GRS, AAP and GGT occurred after the first day of amphotericin B treatment and continued until the fourth day. Following treatment for 4 days with amphotericin B urine AAP activity amounted to 69 +/- 19 U g-1 creatinine, control: 39 +/- 7 U g-1 creatinine (P < 0.05). After 4 days GGT excretion increased to 803 +/- 238 U g-1 creatinine, control: 445 +/- 106 U g-1 creatinine (P < 0.05). At the fourth day NAG excretion was 80 +/- 39 U g-1 creatinine, control: 23 +/- 5 U g-1 creatinine (P < 0.05) and GRS 724 +/- 604 U g-1 creatinine (amphotericin B), control: 276 +/- 158 U g-1 creatinine (P < 0.05). Treatment with amphotericin B decreased the creatinine clearance significantly: 0.94 +/- 0.16 ml-1 min-1 vs. control 1.35 +/- 0.29 ml-1min-1 (P < 0.05). Fractional sodium and potassium excretion was not influenced by amphotericin B. The application of sodium deoxycholate had no influence on urinary renal tubular enzyme activity. The results show that amphotericin B application induces early enzymuria of renal tubule enzymes suggesting damage of proximal renal tubules.     

Pharmacokinetics of oral methotrexate in children

The absorption and disposition kinetics of p.o. methotrexate were studied in 15 children. Serum levels and urinary excretion of methotrexate, as measured by the dihydrofolate reductase inhibition assay, were monitored following a routine p.o. dose (6.3 to 28.1 mg/sq m) administered after an overnight fast. Significant interindividual variability was noted in peak levels (range, 0.27 to 1.1 microM), time to peak (1 to 5 hr), area under the serum concentration-time curve (1.08 to 5.00 microM . hr), and the fraction of the dose absorbed (23 to 95%). Patients taking doses greater than 12 mg/sq m had a more prolonged absorptive phase and absorbed a smaller fraction of their dose, indicating that the mechanism of absorption may be saturable in some patients within the commonly administered dosage range. Urinary excretion was rapid, and the mean renal clearance of methotrexate was 1.6 times greater than was creatinine clearance, consistent with renal tubular secretion of the drug. While the marked degree of variability observed suggests a potential role for therapeutic drug monitoring in optimizing p.o. methotrexate therapy, the critical time points to monitor, the therapeutic and toxic ranges, and the intrapatient consistency of absorption must be defined before it will be practical and useful.