新水溶性nitrosourea系制癌剤ACNUの脳腫瘍患者におけるpharmacokineticsに関する一考察

A CONSIDERATION ON PHARMACOKINETICS OF A NEW WATER-SOLUBLE ANTI-TUMOR NITROSOUREA, ACNU, IN PATIENTS WITH MALIGNANT BRAIN TUMOR

I．はじめに

　悪性脳腫蕩の生解析の解明がなされるようになり化学療法に基礎的な理論が導入され新しい概念の治療法が施行されるようになつてきた。その中心となる薬剤の1つにCCNU^5,6,9,25），BUNC^{2,19,24,27）}Methyl-CCNU^22,23,28）で代表されるニトロソウレア系薬剤があり（Table 1），これらはいずれも脂溶性で血液脳関門を通過しうるcellcycle non specific agent （CCNS）とされ臨床例においても良好な成績の報告がみられる。

　脳腫瘍の化学療法の場合，その使用薬剤の血液脳関門の透過性^13,26）とpharmacokinetics^{3,14,15,17）}は重要な問題となるが，今回われわれは，同じニトロソウレア系薬剤ではあるが，わが国で新しく開発された水溶性ニトロソウレア剤ACNU^1,21）の静注時の髄液移行度ならびにpharmacokineticsについて検討したので報告する。

For the purpose of treatment of brain tumor with ACNU^1,21), 1-(4-amino-2 methylpyrimidin-5- yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydro-chloride, it was examined to correlate of perme-ability in blood-brain-barrier (B. B. B.) with its pharmacokinetics of ACNU.

ACNU 100-150 mg/boby was injected intra-venously into 14 cases of brain tumor. Transition of ACNU into cerebrospinal fluid (CSF) was noted after 5 minutes, showing the maximum value of 0.59 ±0.13 μg/ml after 30 min.

The pharmacokinetic analysis in CSF level was performed according to the one compartment model BMDP 3R Non-Iinear Regression Program³⁾ (Fig. 2) using an IBM 370/125 Computer. The following formula (1) was simulately established from the relation of CSF level with time (hr), and the transition rate constant (k_t) and elimination rate constant (k_e1) were then calculated.

C_p=k_t/k_t-k_e1 A₀(e-k_e1･t-e-k_t･t)……………( 1 )

Consequently, k_t = 1. 85 hr^- and k_e1 =1. 42 hr- were obtained. The half-life (t 1/2) in CSF (ventricle) was estimated at O. 49 hr. The maximum concen-tration in the ventricle was approximately 1 μgml achieved at 37 mins. after the intravenous injection, indicating the transition to be considerably slower in comparison with other tissues. Furthermore, k_el coincided closely with the blood level, sug-gesting some degree of transition had occurred from the blood to CSF.

The phamacokinetic analysis in blood level was performed according to the two compartment open model⁷⁾. The drug-concentration in the central compartment (blood and organs having the same behavior as blood) can be described as the following formula (2), where V₁ is the distribution volume of central compartment, V₂=distribution volume of tissue compartment (all tissues other than central compartment), k₁₂ and k₂₁ =transition rate constant between the two compartments and k_e1=elimination rate constant from the central compartment.

C_p=A_e^-αt+B_e^-βt…………… ( 2 )

Values of A, B, α and β to complete the above formula were obtained from blood levels and times (hr), and k₁₂, k₂₁, k_e1, V₁, V₂, t/2 (half life) and [AUC]₀^∞ were then calculated referring to these known parameters. From the above results, it can be concluded with respect to the in vivo behavior of ACNU i. v. as follows :

(1) The distribution rate is extremely rapid, with half-life of a-phase (αt/2) being 1.3 minutes (0.021 hr).

(2) The elimination rate is also relatively rapid having half life (βt/2) of 35 minutes (0.58 hr).

(3) In comparisons of rate constants, the order was revealed to be k₁₂ k_el k₂₁ in individual cases except for Model-I.

(4) In distribution volume, V₂ was larger than V₁ indicating its higher transition into the tissue compartment.

It is concluded that ACNU transits well into CSF. The authors therefore expect ACNU to be valuable for the treatment of brain tumors.