Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    ISSN: 1432-0843
    Keywords: Key words Erythrocytes ; Oxaliplatin ; Pharmacokinetics ; Plasma binding ; Renal function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The pharmacokinetics (PK) of platinum was investigated and compared in patients with normal (NRF) and impaired renal function (IRF), after they had received oxaliplatin at the recommended dose and delivery modality. Methods: Oxaliplatin was administered at 130 mg/m2 as a 2-h infusion without hydration. Patients were recruited and classified according to their creatinine clearance (CrCl 〉 or 〈 60 ml/min), calculated using the Cockcroft and Gault formula. Blood was taken for PK analysis during and after the infusion. Twenty-three patients were included in the PK analysis (13 NRF and 10 IRF). At inclusion, the median CrCls were 70.5 ml/min (range 63–136) for the NRF group and 42 ml/min (range 27–57) for the IRF group. Three patients underwent a second course of treatment and additional blood sampling for analysis. Platinum levels in the plasma, ultrafiltrate and red blood cells (RBCs) were measured using flameless atomic absorption spectrophotometry (FAAS). Results: Following the administration of oxaliplatin, platinum binding to plasma proteins and RBCs was rapid and extensive; at the end of the 2-h infusion, 27% of the platinum in the plasma remained free (40% bound to RBCs, 33% bound to plasma proteins). Neither the mean maximal concentration (Cmax) of total platinum in the plasma, the mean Cmax of ultrafilterable platinum in the plasma, nor the maximal platinum content in the RBCs differed significantly between the two groups (2.59 vs 2.58 μg/ml, 1.09 vs 1.28 μg/ml and 2.06 vs 2.17 μg/ml, respectively, for patients with NRF vs IRF). After the end of the infusion, levels of total and free (ultrafilterable) platinum in the plasma declined biexponentially. The plasma clearance of both total and free platinum as well as the area under the curve (AUC) of the free platinum fraction correlate with the calculated CrCl (P=9 × 10−3, P=3.1 × 10−5 and P=9 × 10−6, respectively). After a single course of oxaliplatin, toxicities reported in the two groups of patients were similar. Conclusions: Our results are in agreement with the in vitro data concerning the extensive binding of oxaliplatin to plasma proteins and RBCs. They also reveal a strong negative correlation between free drug plasma availability and renal function, with a corresponding positive correlation between clearance of the plasmatic platinum and renal function. Thus, renal impairment entails a greater overall exposure to platinum in the plasma. However, this study failed to elicit any relationship between moderate renal impairment and the acute toxicity associated with oxaliplatin.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    ISSN: 1432-0738
    Keywords: Key words Cyclosporin G  ;  Cyclosporin A  ;  FK506  ;  Cytotoxicity  ;  Cytochrome P-450 3A
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract FK506, cyclosporin A (CsA), and its structural analog cyclosporin G (CsG) are immunosuppressant drugs mainly metabolized by hepatic cytochrome P-450 3A (CYP 3A) oxygenase. FK506 metabolites exhibit greater toxicity than the parent drug, while CsA metabolites are far less toxic than CsA itself. The aim of our study was to compare the toxicity of CsG with CsA and FK506 as a function of CYP 3A induction. Hepatocytes from Wistar rats with or without dexamethasone (DEX) induction (200 mg/kg per day, p.o for 4 days) were used in primary culture. The DEX-inductive effect on CYP 3A was assessed by SDS-PAGE. After 6 h incubation with CsG, CsA or FK506 (5 to 200 μM), cell viability (expressed as IC50), intracellular calcium content and apoptosis were evaluated. Concerning cytotoxicity, IC50 values for CsG, CsA and FK506 were 75, 50 and 180 μM respectively in non-induced cultures, and 150, 120 and 25 μM in induced cultures. For intracellular calcium content, a dose-dependent increase was observed in all cultures. However this increase is more important for CsG and CsA in non-induced cultures (150%) compared to induced cultures (110%) at 150 μM. Conversely for FK506, this increase is greater in induced cultures (150%) than in non-induced cultures (127%). Estimation of the percentage of apoptotic cells shows similar variations. Our results show that the toxicity of the three drugs in rat hepatocytes is dependent on CYP 3A induction: increased for FK506, decreased for CsA and CsG. Moreover, with regard to the three tests used, the toxic effects of CsG are close to those of CsA, indicating that CsG metabolites are also less toxic than the parent drug.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    ISSN: 1432-0738
    Keywords: Key words FK506 ; Cyclosporin A ; Cytochrome P-450 3A ; Toxicity ; In vitro
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tacrolimus (FK506) and cyclosporin A (CsA) are two potent immunosuppressants mainly metabolized by hepatic cytochrome P-450 3A (CYP3A) monooxygenase. The aim of this study was to compare the toxic effects of the two drugs on hepatocytes in primary culture as a function of their metabolism and to explore the variations of cytotoxicity when both drugs are associated. The cytotoxicity of FK506 and CsA, as expressed by their IC50 values, was of the same order but with a switch according to whether hepatocytes were induced or uninduced by dexamethasone, CsA being more toxic in its native form and FK506 through its metabolism. Similar results were obtained with the intracellular calcium content. When both drugs were associated at their IC50 values, the expected additive cytotoxic effect was not observed. Moreover, when small quantities of FK506 were added to CsA at its IC50, cell viability improved in the induced cultures. It is hypothesized that the interaction between the two drugs relies on a mechanism involving both competition of FK506 and CsA for CYP3A and of their immunophilin complexes for a common site on the calcineurin-calmodulin complex.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    ISSN: 1432-0738
    Keywords: Key words Nephrotoxicity ; LLC-PK1 cells ; FK506 ; Cyclosporin A ; ATP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract FK506 and cyclosporin A (CsA) are two potent immunosupressants with similar toxicity profile. Nephrotoxicity is the main adverse effect of both compounds. The aim of this study is to compare the in vitro nephrotoxic effects on renal epithelial cell line LLC-PK1 by measuring cell viability and energy status as evaluated by concentrations of ATP and ATP metabolites. Cell viability (expressed as IC50 was assessed via thiazolyl blue (MTT) assay after incubation for 4–24 h with FK506 or CsA. ATP and its metabolites were determined by HPLC after 4 and 6 h incubation with FK506 or CsA alone at the respective IC50. Both FK506 and CsA decreased cell viability to similar extents, in a dose- and time-dependent manner. After 4 h incubation, both drugs decreased ATP levels (−25%) and increased uric acid levels. However, the latter percentage increase was twofold higher with CsA (18%) than with FK506 (9%). The energy charge, calculated according to levels of adenine nucleotides, was decreased by 10% in FK506-treated cells and by 27% in CsA-treated cells. At the end of 6-h incubation, FK506-treated cells maintained ATP levels coupled with energy charge at near control levels whereas the levels were 32% lower in CsA treated cells. Compared to the 4 h-incubation, the increase in uric acid was similar for FK506 but was doubled with CsA. The decrease in cell integrity and ATP depletion induced by CsA in LLC-PK1 cells was only transiently observed with FK506. By preserving energy status, FK506 leads to fewer metabolic disturbances than CsA in the renal epithelial cell line LLC-PK1, demonstrating a minor potential nephrotoxicity.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...