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Biomedical subjects

K Nooter

Publications and source records attributed to K Nooter.

At least 109 records · Page 6Linked to original sources
PubMed1987

Kinetics of daunomycin in leukemia cells and leukocytes in vivo in the rat.

The capability of nucleated blood cells and leukemic cells to transport daunomycin (DNR) to target tissues in the body was investigated in the rat. The in vivo distribution kinetics of DNR entrapped in leukemia cells (brown Norway acute myeloid leukemia, BNML) or in nucleated bone marrow cells, which had been exposed to DNR (0.2 mg/5 X 10(7) cells) in vitro, were determined. It was found that BNML leukemia cells and normal bone marrow cells take up DNR according to a linear pattern up to 400 micrograms/5 X 10(7) cells. When these DNR loaded cells are infused into the rat, dose dependent distribution kinetics are observed. Compared to i.v. injection of the same dosage, cell-bound DNR leads to a higher concentration and a higher tissue area under the curve of DNR in the liver (P less than 0.05) and the spleen (P less than 0.05), while equal levels are attained in bone marrow. Lower concentrations and area under the curve of DNR are observed in cardiac tissue of normal rats (P less than 0.001) and leukemic rats (P less than 0.05). It is concluded that DNR entrapped into marrow and leukemia cells follows different kinetics from free DNR in plasma.

Animals↗
PubMed1986

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate.

The absorption, distribution, and elimination kinetics of low-dose p.o. methotrexate (MTX) were repeatedly studied in 19 children during maintenance treatment of childhood acute lymphoblastic leukemia. Plasma concentrations, urinary elimination, and bone marrow concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were monitored during 24 h following a routine p.o. dose (30 mg/m2) using high-pressure liquid chromatography. Significant interindividual variability was found in time to peak concentration (30-180 min), peak concentration (0.41-2.77 microM), and to a lesser extent the half-lives (t1/2 alpha: 32.8-86.1 min; t1/2 beta: 43.6-350.0 min; t1/2 absorption: 25.2-60.3 min) and plasma area under the concentration-time curve from zero to infinity (195.6-818.5 microM.min). Significant amounts of 7-OH-MTX were detected in plasma, with a mean area under the concentration-time curve from zero to infinity of 208 microM.min compared with 365.6 microM.min for MTX. High concentrations of 7-OH-MTX were present in bone marrow 24 h after oral MTX (15/19 patients) and were at least five fold those in plasma and three fold the concentration of MTX in bone marrow. In four patients occasionally neither MTX nor metabolite could be detected. Repeated examination of these pharmacokinetic parameters in plasma and bone marrow showed that the intraindividual variability was small.

Administration, Oral↗
PubMed1986

Quantitative evaluation of intracellular uptake of daunorubicin in acute myeloid leukemia: a method analysis.

Critical technical parameters to establish a reliable method for quantifying the intracellular content of anthracyclines were evaluated in patients with acute myelocytic leukemia (AML); two methods were used for the isolation of leukocytes from the peripheral blood and two methods, for the extraction of daunorubicin (DNR), daunorubicinol (DOL), and doxorubicin (DOX) from these cells, followed by drug analysis using high-performance liquid chromatography (HPLC). At 0-4 degrees C the recovery of leukocytes after methylcellulose separation was low (64%). Cold hypotonic lysis gave better recovery (100%) when performed at the same temperature. After low-volume (2 ml extraction mixture) drug extraction from isolated leukocytes, the recoveries of DNR, DOL, and DOX from the cells were low, and they were inversely related to the cellularity of the sample, irrespective of the amount of drug in the cells. With high-volume extraction (5 ml extraction mixture) the recoveries were better (up to 95%), but they remained dependent on the cellularity. A correction factor accounting for these cellularity-related recoveries was applied to calculate the DNR and DOL contents of the leukocytes. Finally, using this information, plasma and cellular DNR and DOL levels were measured in seven patients with AML during their first course of remission induction therapy. The cellular DNR levels appeared to vary over a broad range and did not correlate with plasma pharmacokinetics.

Adolescent↗
PubMed1986

Tissue distribution and myelotoxicity of daunomycin in the rat: rapid bolus injection vs continuous infusion.

The pharmacokinetic and cytotoxic behaviour of daunomycin in rats (7.5 mg/kg) when administered as an i.v. bolus injection were compared with those of a 3-hr infusion. After an i.v. bolus injection, the plasma drug levels decreased triphasically (t1/2 alpha = 0.8 min, t1/2 beta = 29.6 min and t1/2 gamma = 9.9 hr). The organs showed two types of concentration/time curves. One was found in the lungs, liver, kidneys and heart and had an initial high drug concentration followed by a relatively rapid elimination. The other was shown by the hemopoietic tissues (spleen and bone marrow): the drug uptake phase lasted longer (about 1.5 hr) and the elimination was slower. In general, daunomycin infusion led to substantially lower plasma and tissue levels, including in the heart, liver and kidneys. Again the hemopoietic tissues behaved in a different way: in spleen and bone marrow almost equal drug levels were obtained after daunomycin infusion as compared to a bolus injection. The myelotoxicity after daunomycin treatment was assessed by CFU-S (colony forming units-spleen) survival: the bolus injection killed as many CFU-S as did infusion (mean +/- S.D.: 11.8 +/- 5.3 CFU-S survival versus mean +/- S.D.: 13.5 +/- 2.4). Thus, it can be predicted that daunomycin infusion will lead to less cardiotoxicity but to an equal bone marrow suppression.

Animals↗
PubMed1985

Effect of X-irradiation on the pharmacokinetics of methotrexate in rats: alteration of the blood-brain barrier.

This study was designed to evaluate the effects of brain irradiation on the permeability of the blood-brain barrier for methotrexate (MTX). Female WAG/Rij rats were cranially irradiated with a single dose of 20 Gy of 300 kV X-rays. At different times (1-15 days) after the exposure the rats were injected intravenously with MTX (25 mg/kg body wt). Irradiation had hardly any effect on the MTX concentrations in the plasma, heart and kidneys as determined by high-performance liquid chromatography. However, irradiation resulted in a significant increase of MTX (determined by 125I-radioimmunoassay) in brain tissue per gram wet weight (187.6 +/- 17.9 pmol/g vs 46.4 +/- 29.3 pmol/g in unirradiated brain). This change in permeability of the blood-brain barrier lasted for about 9 days. The MTX elimination from the irradiated brain was the same as that from the non-irradiated brain. This indicates that only the MTX uptake and not the elimination by the brain was affected by the irradiation treatment.

Animals↗
PubMed1985

Decreased intestinal absorption of methotrexate in the rat following repeated oral dosing.

The absorption of methotrexate (MTX) following single and repeated oral administrations was investigated in the rat and compared with that after intravenous injections. The absorption of intermediate dose MTX was poor (14.7%), both after single gift (25 mg X kg-1) and when given repeatedly at 72-hour intervals (3 X 25 mg X kg-1). Repeated oral administration did not produce higher plasma concentrations of MTX in spite of decreased elimination as a result of impaired renal clearance. It is concluded from these experiments that repeated oral administration of MTX when spaced 72 hours apart leads to a deterioration of the already incomplete intestinal absorption of the drug in the rat.

Administration, Oral↗
PubMed1985

Differences in the pharmacokinetics of daunomycin in normal and leukemic rats.

We compared the pharmacokinetics of daunomycin (7.5 mg/kg i.v. bolus injection) in normal and leukemic rats using a leukemia model which resembles acute myeloid leukemia in humans. Due to a more rapid decrease in plasma concentration, the area under the plasma concentration/time curve (AUC) for up to 2 h after drug injection was smaller (2.2 times) in the leukemic rats than that for normals. However, due to higher plasma levels during the drug elimination phase, the total AUC0----infinity was somewhat larger (1.3 times) in the leukemic rats. In the leukemia-infiltrated organs (spleen, liver, and lungs), significantly higher daunomycin concentrations (per gram wet weight) were found than in those obtained from normal rats. In contrast, femoral bone marrow from leukemic rats contained less daunomycin (per 10(9) nucleated cells) than did normal marrow. Quantification of the daunomycin uptake in vitro by flow cytometry showed that leukemic cells from bone marrow and spleen have an equal net drug uptake. Our data suggest that, in the presence of a high leukemic cell load, the intravenously injected daunomycin is rapidly taken up and retained by the leukemic tumor mass in, e.g., spleen, liver, and lungs, and that, as a consequence of this, the femoral marrow functions as a kind of pharmacological sanctuary.

Animals↗
PubMed1984

Blood and tissue distribution of cyclosporin A after a single oral dose in the rat.

After a single oral dose of cyclosporin A (82 mg/kg) in rats, tissue (kidneys liver and brain) and blood levels reached maximum values (approximately 80 micrograms/g and 3.5 micrograms/ml) between 3 and 7 h after drug administration. Drug elimination continued for at least 5 days. The 24-h urine and bile elimination was 2% for each.

Administration, Oral↗
PubMed1984

Repeated daunomycin administration in rats. Pharmacokinetics and bone marrow toxicity.

In the experiments described here, rats received three IV bolus injections (7.5 mg/kg) of daunomycin. The plasma data obtained after a single IV injection could be described by a two-compartment open model with t1/2 alpha and t1/2 beta values of 18.4 and 472.1 min. Of the tissues, the lungs contained the most daunomycin per gram of tissue, followed by the kidneys, liver, heart, and spleen. Daunomycinol was the main metabolic product and no substantial differences were found in daunomycinol content among the different organs. For all tissues and plasma, higher drug concentration values than would be expected on the basis of accumulation alone were observed after the second but not after the third injection. The cumulative urine excretion of daunomycin and daunomycinol remained essentially unchanged after one, two, and three daunomycin injections. However, the cumulative bile excretion increased after repeated daunomycin administration. The experiments in which the myelotoxicity was assessed by CFU-S survival after daunomycin treatment showed that three successive daunomycin administrations lead to a proportional reduction in stem cells.

Animals↗
PubMed1984

Evidence for a possible dose-dependent pharmacokinetics of Cyclosporin-A in the rat.

Cyclosporin-A (Cy-A) was administered to rats intravenously (i.v.) at different dosages (20, 40 and 80 mg/kg body weight). At the lower dose (20 mg/kg), the blood levels decreased biphasically and could be described by an open linear two-compartment model with excretion from the central compartment only. The t 1/2 values for the alpha-distribution and beta-elimination phases were about 6 min and 16.5 h, respectively. At higher dose levels (40 and 80 mg/kg), the involvement of an additional compartment became apparent. The blood concentration/time data sets obtained with 40 and 80 mg/kg doses were best described by an open linear three-compartment model. The 24-h urine and bile excretions were in the order of 10 and 20% of the total administered dose. The values for the normalized areas under the plasma concentration/time curves obtained at different Cy-A doses (20, 40 and 80 mg/kg) were about 1, 3 and 25, respectively.

Animals↗
PubMed1984

Long persistence of doxorubicin in human skin after extravasation.

Extravasation of doxorubicin (DXR) from a dorsal hand vein is described. At 28 days following this event, high dermal concentrations of DXR were still present, not only at the injection site (1.7 X 10(-6) M X g-1) but also at a distance of 5 cm (0.4 X 10(-6) m X g-1. This long persistence of DXR in the skin necessitates ample excision of the skin following severe extravasation of the drug.

Adult↗
PubMed1983

Quantitative flow cytometric determination of anthracycline content of rat bone marrow cells.

Flow cytometry was used to determine the daunomycin content of rat bone marrow cells after incubation in vitro. The spontaneous fluorescence of daunomycin was measured upon excitation with laser light at 488 nm. Forward and perpendicular light scatters of the cells were simultaneously measured to allow identification of granulocytic and lymphocytic subpopulations. A linear relationship was found for a 30-min exposure between the drug concentration (ranging from 0.2 to 3 micrograms/ml) in the incubation medium and the fluorescence intensity for both lymphocytes and granulocytes. Dead cells contaminating cell suspensions showed several times higher daunomycin fluorescence than did viable cells. In fixed cells, the fluorescence reflects daunomycin bound to DNA, since the fluorescence intensity of daunomycin-treated fixed cells returns to the level of unstained cells after DNase treatment. Quantitation of the cellular drug concentration was done by exposing cells in vitro to varying doses of [3H]daunomycin. At each drug concentration, the fluorescence intensity of the cells was measured using flow cytometry. Granulocytes and lymphocytes were sorted on the basis of light scatter. The amount of intracellular drug was determined for both cell populations at each drug dose by measuring the radioactivity in 600,000 sorted cells. The concentration per cell was on the order of 10(-18) mol. For both the granulocytic and the lymphocytic subpopulations, a linear relationship was found between drug-related radioactivity and fluorescence intensity.

Animals↗
PubMed1979

Characterization of a type-C virus produced by co-cultures of human leukemic bone-marrow and fetal canine thymus cells.

The putative human helper virus SKA-21/A204V, isolated by Nooter et al. in 1977 from human leukemic bone-marrow cells following co-culture with normal fetal canine thymus cells, Cf2th, has been characterized with respect to its major viral core protein, reverse transcriptase, and nucleic acid sequences. The results of these analyses show that this virus is not distinguishable from the woolly monkey type-C virus, SSAV-1, by the techniques employed.

Animals↗