Basic study of pharmacokinetic model analysis of anti-cancer agent, dacarbazine, using rats

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  • 抗悪性腫瘍薬・ダカルバジンのラットを用いた薬物動態学的モデル解析の基礎的検討
  • コウアクセイ シュヨウヤク ・ ダカルバジン ノ ラット オ モチイタ ヤクブツ ドウタイガクテキ モデル カイセキ ノ キソテキ ケントウ

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Dacarbazine is a therapeutic agent for melanoma of alkylating anti-tumor agents. In this study, we examined its pharmacokinetic characteristics using experimental animals and investigated using various pharmacokinetic model analysis methods. The pharmacokinetic behavior of the drug can be simulated in the various treatment routes and/or schedules and provide basic information on medical treatment. The pharmacokinetics of dacarbazine followed a 2-compartment pharmacokinetic model, namely some organs being rapidly distributed and some organs taking a long time, resulting in a relatively large volume of distribution. No accumulation of dacarbazine was observed in the body after intravenous administration once daily for 5 days, which is the standard treatment schedule in clinical practice. It shows effective pharmacokinetics as drugs with a concentration-dependent effect. Dacarbazine is usually administered rapidly intravenous bolus or by iv infusion, though it is considered that dacarbazine shows similar pharmacokinetics and is effective even in the extravascular route where rapid absorption, with an absorption rate constant (ka) of about 0.5 min-1 or more, can be obtained. Using the pharmacokinetic modeling technique, it is possible to predict the pharmacokinetics when administered under various conditions, and further to predict the degree of effect onset and the time transition (duration) of the effect. In addition, by proceeding with the study, it is possible to estimate how the pharmacokinetics will change and how the effects of the drug will be affected when combination therapy is given as compared to monotherapy. Similarly, when physiological conditions change, such as age and pathological condition, the outcome of drug therapy is estimated by how the pharmacokinetics and drug effects are affected or hardly affected.

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