148 research outputs found
Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans
Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting
protein that is abundantly present in biliary ductal cells and epithelial
cells lining the gastrointestinal tract. Here, we have determined the role
of P-gp in the metabolic disposition of the antineoplastic agent docetaxel
(Taxotere) in humans. Pharmacokinetic profiles were evaluated in five
cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2
i.v. over a 1-h period) and in combination with a new potent inhibitor of
P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition
half-life and total plasma clearance of docetaxel were not altered by
treatment with oral R101933 (P > or = 0.27). The cumulative fecal
excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14%
(mean +/- SD) of the dose with the single agent to less than 0.5% in the
presence of R101933 (P = 0.0016). Levels of the major cytochrome P450
3A4-mediated metabolites of docetaxel in feces were significantly
increased after combination treatment with R101933 (P = 0.010), indicating
very prominent and efficient detoxification of reabsorbed docetaxel into
hydroxylated compounds before reaching the systemic circulation. It is
concluded that intestinal P-gp plays a principal role in the fecal
elimination of docetaxel by modulating reabsorption of the drug after
hepatobiliary secretion. In addition, the results indicate that inhibition
of P-gp activity in normal tissues by effective modulators, and the
physiological and pharmacological consequences of this treatment, cannot
be predicted based on plasma drug monitoring alone
Measurement of fraction unbound paclitaxel in human plasma
The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly
nonlinear, with disproportional increases in systemic exposure with an
increase in dose. We have recently shown that Cremophor EL, the
formulation vehicle used for i.v. administration of paclitaxel, alters
drug distribution as a result of micellar entrapment of paclitaxel, and we
speculated that the free drug fraction (fu) is dependent on dose and
time-varying concentrations of Cremophor EL in the central plasma
compartment. To test this hypothesis, a reproducible equilibrium dialysis
method has been developed for the measurement of paclitaxel fu in plasma.
Equilibrium dialysis was performed at 37 degrees C in a humidified
atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments
were carried out with 260-microliter aliquots of plasma containing a
tracer amount of [G-(3)H]paclitaxel with high-specific activity against an
equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were
measured by both reversed-phase HPLC and liquid scintillation counting.
Using this method, fu has been measured in three patients receiving three
consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and
225 mg/m(2) and found to range between 0.036 and 0.079. The method was
also used to define concentration-time profiles of unbound drug, estimated
from the product of the total plasma concentration and fu
Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function
In the present work, we studied the pharmacokinetics and metabolic
disposition of [G-(3)H]paclitaxel in a female patient with recurrent
ovarian cancer and severe renal impairment (creatinine clearance:
approximately 20 ml/min) due to chronic hypertension and prior cisplatin
treatment. During six 3-weekly courses of paclitaxel at a dose level of
157.5 mg/m(2) (viz. a 10% dose reduction), the renal function remained
stable. Pharmacokinetic evaluation revealed a reproducible and
surprisingly high paclitaxel area under the plasma concentration-time
curve of 26.0 +/- 1.11 microM.h (mean +/- S.D.; n = 6; c.v. = 4.29%), and
a terminal disposition half-life of approximately 29 h. Both parameters
are substantially increased ( approximately 1.5-fold) when compared with
kinetic data obtained from patients with normal renal function. The
cumulative urinary excretion of the parent drug was consistently low and
averaged 1.58 +/- 0.417% (+/- S.D.) of the dose. Total fecal excretion
(measured in one course) was 52.9% of the delivered radioactivity, and
mainly comprised known mono- and dihydroxylated metabolites, with
unchanged paclitaxel accounting for only 6.18%. The plasma area under the
plasma concentration-time curve of the paclitaxel vehicle Cremophor EL,
which can profoundly alter the kinetics of paclitaxel, was 114.9 +/- 5.39
microl.h/ml, and not different from historic data in patients with normal
or mild renal dysfunction. Urinary excretion of Cremophor EL was less than
0.1% of the total amount administered. These data indicate that the
substantial increase in systemic exposure of the patient to paclitaxel
relates to decreased renal metabolism and/or urinary elimination of polar
radioactive species, most likely lacking an intact taxane ring fragment
Charge Fluctuations in Quantum Point Contacts and Chaotic Cavities in the Presence of Transport
We analyze the frequency-dependent current fluctuations induced into a gate
near a quantum point contact or a quantum chaotic cavity. We use a current and
charge conserving, effective scattering approach in which interactions are
treated in random phase approximation. The current fluctuations measured at a
nearby gate, coupled capacitively to the conductor, are determined by the
screened charge fluctuations of the conductor. Both the equilibrium and the
non-equilibrium current noise at the gate can be expressed with the help of
resistances which are related to the charge dynamics on the conductor. We
evaluate these resistances for a point contact and determine their
distributions for an ensemble of chaotic cavities. For a quantum point contact
these resistances exhibit pronounced oscillations with the opening of new
channels. For a chaotic cavity coupled to one channel point contacts the charge
relaxation resistance shows a broad distribution between 1/4 and 1/2 of a
resistance quantum. The non-equilibrium resistance exhibits a broad
distribution between zero and 1/4 of a resistance quantum.Comment: 9 pages, two-column Revtex, 6 figures include
Perinatal exposure to polychlorinated biphenyls and dioxins through dietary intake
Polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo p-dioxins and dibenzofurans) are potentially hazardous compounds. Since food is the major source (>90%) for the accumulation of PCBs and dioxins in the human body, food habits in women determine the degree of fetal exposure and levels in human milk. In order to investigate an association between dietary intake and PCB and dioxin levels in human milk and PCB levels in maternal and cord plasma, the food intake of 418 Dutch women during pregnancy was recorded using semi-quantitative food frequency questionnaires. After adjusting for covariates, a weak association was found between the estimated dietary intake of 2,3,7,8-tetrachlorodibenzo p-dioxin (2,3,7,8-TCDD), dioxins, and planar PCBs and their corresponding levels in breast milk. The estimated dietary intake of 2,3,7,8-TCDD, dioxins, and planar PCBs was also related to the PCB levels in maternal and cord plasma. Dairy products accounted for about half and industrial oils for about a quarter of the estimated 2,3,7,8-TCDD, dioxin, and the planar PCB intake. It is concluded that the contribution of a pregnancy related diet to PCB and dioxin levels in human milk and to PCB levels in maternal and cord plasma is relatively low. Decrease of exposure to PCBs and dioxins of the fetus and the neonate probably requires long-term reduction of the intake of these pollutants. Substitution of normal cheese by low-fat cheese and the use of vegetable oils instead of fish oils in the preparation of foodstuffs by the food industry could contribute to a reduced intake of PCBs and dioxins
Ageing and latent CMV infection impact on maturation, differentiation and exhaustion profiles of T-cell receptor gammadelta T-cells
Ageing is a broad cellular process, largely affecting the immune system, especially T-lymphocytes. Additionally to immunosenescence alone, cytomegalovirus (CMV) infection is thought to have major impacts on T-cell subset composition and exhaustion. These impacts have been studied extensively in TCRαβ+ T-cells, with reduction in naive, increase in effector (memory) subsets and shifts in CD4/CD8-ratios, in conjunction with morbidity and mortality in elderly. Effects of both ageing and CMV on the TCRγδ+ T-cell compartment remain largely elusive. In the current study we investigated Vγ- and Vδ-usage, maturation, differentiation and exhaustion marker profiles of both CD4 and CD8 double-negative (DN) and CD8+TCRγδ+ T-cells in 157 individuals, age range 20–95. We observed a progressive decrease in absolute numbers of total TCRγδ+ T-cells in blood, affecting the predominant Vγ9/Vδ2 population. Aged TCRγδ+ T-cells appeared to shift from naive to more (late-stage) effector phenotypes, which appeared more prominent in case of persistent CMV infections. In addition, we found effects of both ageing and CMV on the absolute counts of exhausted TCRγδ+ T-cells. Collectively, our data show a clear impact of ageing and CMV persistence on DN and CD8+TCRγδ+ T-cells, similar to what has been reported in CD8+TCRαβ+ T-cells, indicating that they undergo similar ageing processes
Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications
We have determined the in vitro and in vivo cellular distribution of the
antineoplastic agent paclitaxel (Taxol) in human blood and the influence
of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In
the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004
(mean+/-SD). The addition of CrEL at concentrations corresponding to peak
plasma levels achieved after the administration of paclitaxel (175 mg/m2
i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in
the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments
revealed that this effect was caused by reduced erythrocyte uptake of
paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound
present in CrEL. Using equilibrium dialysis, it was shown that the
affinity of paclitaxel for tested matrices was (in decreasing order) CrEL
> plasma > human serum albumin, with CrEL present at or above the critical
micellar concentration (approximately 0.01%). Our findings in the present
study demonstrate a profound alteration of paclitaxel accumulation in
erythrocytes caused by a trapping of the compound in CrEL micelles,
thereby reducing the free drug fraction available for cellular
partitioning. It is proposed that the nonlinearity of paclitaxel plasma
disposition in patients reported previously should be reevaluated
prospectively by measuring the free drug fractions and whole blood:plasma
concentration ratios
Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL
Background: Several clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cisplatin is associated with important schedule-dependent differences in toxicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting that a pharmacodynamic interaction might have occurred. Materials and methods: In order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood leukocytes and a panel of tumor and non-malignant cell lines with paclitaxel and docetaxel, as well as with their respective formulation vehicles Cremophor EL and Tween 80. Results: Our results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells. Conclusion: The present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contribute to the reduced cisplatin-associated myelotoxicity observed in the clinical combination chemotherapy studies with paclitaxel and docetaxel
Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin
In this study, 11 patients with solid tumors were randomized to receive
irinotecan (CPT-11; 200 mg/m2) as a 90-min i.v. infusion, immediately
followed by cisplatin (CDDP; 80 mg/m2) as a 3-h i.v. infusion in the first
course and the reversed sequence in the second course or vice versa. No
significant differences in any toxicity were observed between the
treatment schedules (decrease in absolute neutrophil count, 74.7 +/- 18.3
versus 80.3 +/- 18.0%; P = 0.41). CPT-11 lactone clearance was similar to
single agent data and not significantly different between study courses
(60.4 +/- 17.1 versus 65.5 +/- 16.3 liter/h/m2; P = 0.66). The kinetic
profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide,
7-ethyl-10-[4-N-(5-aminopentanoic
acid)-1-piperidinolcarbonyloxycamptothecine (APC), and
7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were
also sequence independent (P > or = 0.20). In addition, CPT-11 had no
influence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus
50.3 +/- 18.6 liter/h/m2; P = 0.08) and the platinum DNA-adduct formation
in peripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/-
1.62 pg Pt/microg DNA; P = 0.41). These data indicate that the toxicity of
the combination CPT-11 and CDDP is schedule independent and that there is
no mutual pharmacokinetic interaction
The value of inquiring about functional impairments for early identification of inflammatory arthritis: A large cross-sectional derivation and validation study from the Netherlands
Objectives Healthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly considered as helpful and could be incorporated in online tools to assist healthcare professionals, but first their discriminative ability must be assessed. As part of this effort, we evaluated whether inquiring about functional impairments could aid early IA identification. Design Cross-sectional derivation and validation study. Setting Data from two Early Arthritis Recognition Clinics (EARC) in the Netherlands were studied, which are easy access outpatient rheumatology clinics intermediary between primary and secondary care for patients in whom general practitioners suspect but are unsure about IA presence. Participants Between 2010 and 2014, 997 patients consecutively visited the Leiden-EARC (derivation cohort). Patients c
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