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.
OBJECTIVE
We previously reported that the product of the area under the plasma concentration-time curve (AUC(p)) and a toxicity factor, which in turn was defined as the product of the apparent ratio of tissue to plasma concentration (Kp(app)) and the apparent hydrolysis rate constant (k(hydrolysis)), 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 Kp(app) at steady state were determined. k(hydrolysis) 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 AUC(p) and AUC for the bone marrow but was fitted by a combination of AUC(p) and the toxicity factor (r = 0.908, P < 0.001).


CONCLUSIONS
The product of AUC(p) and the toxicity factor is a useful predictor of the degree of toxicity of oxaliplatin as has been observed with other platinum drugs.
Hanada
Kazuhiko
K
Department of Biopharmaceutics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. hanada@my-pharm.ac.jp
Suda
Makoto
M
Kanai
Norihito
N
Ogata
Hiroyasu
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D001806:Blood Urea Nitrogen; D001853:Bone Marrow / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006868:Hydrolysis; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D000077150:Oxaliplatin; D010976:Platelet Count; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin