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  • 1
    Electronic Resource
    Electronic Resource
    Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients (1996)
    Springer
    Cancer chemotherapy and pharmacology 39 (1996), S. 131-137 
    Details
    ISSN: 1432-0843
    Keywords: Key words Unchanged cisplatin ; Nephrotoxicity ; Pharmacokinetics ; Pharmacodynamics ; Maximum plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary β2-microglobulin (BMGp and BMGu), urinary N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dtmax), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 μg/ml in a standard continuous infusion schedule over 2 h and 4 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050548
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determinant in vivo (1997)
    Springer
    Cancer chemotherapy and pharmacology 40 (1997), S. 11-18 
    Details
    ISSN: 1432-0843
    Keywords: Key words Unchanged cisplatin ; Nephrotoxicity ; Pharmacokinetic/pharmacodynamic relationship ; Area under the concentration-time curve (AUC)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Purpose: The major pharmacokinetic parameters of unchanged cisplatin (CDDP) related to nephrotoxicity were evaluated in rats in vivo using a pharmacodynamic model. Methods: CDDP was administered according to various dosing schedules (single bolus, intermittent bolus, or continuous infusion). Unchanged CDDP in plasma and urine was quantified using high-performance liquid chromatography (HPLC). The pharmacokinetics were assessed by model-independent methods. The relationship between pharmacokinetics and BUN levels was evaluated using a sigmoid maximum response (Emax) model. Results: Unchanged CDDP showed linear pharmacokinetics after single bolus injections of 1 to 5 mg/kg CDDP. Nephrotoxicity was ameliorated following intermittent bolus injection (1 mg/kg per day for 5 days) and continuous infusions (over 2 and 3 h) of the same CDDP doses (5 mg/kg), although these dosing schedules did not change the area under the concentration-time curve (AUC), total clearance (Clt), urinary excretion of unchanged CDDP or kidney platinum levels significantly. The maximum BUN level, as a nephrotoxicity marker, showed dose-related increases after single bolus injection of 1 to 5 mg/kg CDDP and after 3-h infusion of 5 to 25 mg/kg. The pharmacodynamic relationship between the maximum BUN level and Cmax and between the maximum BUN level and AUC were apparently different between single bolus injection and 3-h infusion. The maximum BUN level was related to the AUC calculated by plasma concentrations of unchanged CDDP greater than the threshold level (AUC〉Cmin), a relationship most successfully described by the signoid Emax model, regardless of CDDP dose and schedule. The plasma threshold level of unchanged CDDP was determined as 0.9 μgPt/ml in rats. Conclusions: The present results substantiated the importance of C×T (AUC) value as an indicator of CDDP-induced nephrotoxicity in vivo as well as of tumor cell-killing effect of CDDP in vitro. The AUC〉Cmin of unchanged CDDP was found to be an important pharmacokinetic parameter predicting CDDP nephrotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050618
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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