ABSTRACT
Purpose
We previously reported that the product of the area under the plasma concentration–time curve (AUCp) and a toxicity factor, which in turn was defined as the product of the apparent ratio of tissue to plasma concentration (Kpapp) and the apparent hydrolysis rate constant (khydrolysis), was a determinant of the different degrees of toxicities induced by platinum drugs, cisplatin, carboplatin and nedaplatin. We tested this model with oxaliplatin.
Methods
Oxaliplatin was administered to rats by intravenous bolus or infusion, and the linearity of pharmacokinetics, total clearance and the Kpapp at steady state were determined. khydrolysis was determined in vitro. Nephrotoxicity was estimated from blood urea nitrogen (BUN) level and myelosuppression from platelet count.
Results
The platelet count decreased dose-dependently, but BUN did not increase significantly. The degree of decrease in platelet count caused by oxaliplatin and the other three platinum drugs was not explained by the differences of AUCp and AUC for the bone marrow but was fitted by a combination of AUCp and the toxicity factor (r = 0.908, P < 0.001).
Conclusion
The product of AUCp and the toxicity factor is a useful predictor of the degree of toxicity of oxaliplatin as has been observed with other platinum drugs.
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Abbreviations
- oxaliplatin:
-
1R,2R-diaminocyclohexane-oxalatoplatinum(II)
- cisplatin:
-
cis-diamminedichloro-platinum (II)
- carboplatin:
-
cis-diammine 1-1 cyclobutane-dicarboxylato-platinum (II)
- nedaplatin:
-
cis-diammine glycolate-platinum (II)
- CLtot :
-
total clearance
- AUCp :
-
area under the concentration–time curve for plasma concentration of unchanged platinum drug
- AUCt :
-
area under the concentration–time curve for concentration of unchanged platinum drug in the tissue
- Kpapp :
-
apparent ratio of tissue concentration of unchanged drug to plasma concentration under steady-state conditions
- khydrolysis :
-
apparent first-order rate constant of hydrolysis of unchanged platinum drug
- Vdt :
-
volume of distribution of unchanged compound in the tissue
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Hanada, K., Suda, M., Kanai, N. et al. Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives. Pharm Res 27, 1893–1899 (2010). https://doi.org/10.1007/s11095-010-0189-4
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DOI: https://doi.org/10.1007/s11095-010-0189-4