Supko J, Malspeis L
Int J Oncol. 1995 Oct;7(4):847-54. doi: 10.3892/ijo.7.4.847.
Genistein (GEN) has recently generated considerable interest as a potential agent for the prevention and treatment of cancer. The present investigation was undertaken to determine if the concentrations of drug shown to inhibit the growth of human tumor cell lines by 50% in vitro (IC50=2-27 mu g/ml) can be achieved and sustained systemically in mice. We found that GEN plasma levels decreased biexponetially from 64 mu g/ml to 0.55 mu g/ml during the initial 40 min after i.v. injection of a 52 mg/kg dose. Mean half-lives of the two initial disposition phases were 2.5+/-0.4 min and 7.1+/-1.1 min in mice treated with doses of 9-52 mg/kg. Plasma profiles of i.v. GEN exhibited a prominent secondary peak near 78 min followed by a terminal decay phase with a 39.5+/-16.8 min half-life. Although these features are suggestive of enterohepatic cycling, the mean apparent total plasma clearance of GEN (66.5+/-7.3 ml/min/kg) was nevertheless similar to hepatic blood flow. The systemic availability of GEN from a 180 mg/kg p.o. dose, which afforded 1.1 mu g/ml peak plasma concentration, was only 12%. Thus, bolus i.v. and p.o. administration of GEN failed to either achieve or adequately sustain plasma levels of the drug within the target range established by in vitro antitumor studies. Plasma levels resulting from i.p. injection of a 185 mg/kg dose were 5-times greater on average than achieved by the p.o. route. While the plasma concentration exceeded the IC50 values for the majority of human cancer cell lines responsive to GEN for only a short period of time, drug levels remained above 2 mu g/ml, the IC50 of the most sensitive cell lines, for 4 h. Extrapolation from the single dose study suggests that repetitive i.p. injection of at least 200 mg/kg GEN every 8 h will afford continuous systemic exposure to potentially cytostatic concentrations of the drug against these cell lines. This information should facilitate efforts to assess the effectiveness of GEN in appropriate in vivo tumor models.
染料木黄酮（GEN）作为一种潜在的癌症预防和治疗药物，最近引起了广泛关注。本研究旨在确定在体外能抑制人肿瘤细胞系生长50%的药物浓度（IC50 = 2 - 27μg/ml）在小鼠体内是否能够达到并维持在全身系统中。我们发现，静脉注射52mg/kg剂量后最初40分钟内，GEN血浆水平呈双指数下降，从64μg/ml降至0.55μg/ml。在接受9 - 52mg/kg剂量治疗的小鼠中，两个初始处置阶段的平均半衰期分别为2.5±0.4分钟和7.1±1.1分钟。静脉注射GEN的血浆曲线在78分钟左右出现一个明显的次级峰，随后是一个终末衰减阶段，半衰期为39.5±16.8分钟。尽管这些特征提示存在肝肠循环，但GEN的平均表观总血浆清除率（66.5±7.3ml/min/kg）仍与肝血流量相似。口服180mg/kg剂量的GEN，其血浆峰值浓度为1.1μg/ml，系统利用率仅为12%。因此，静脉推注和口服GEN均未能在体外抗肿瘤研究确定的目标范围内达到或充分维持药物的血浆水平。腹腔注射185mg/kg剂量产生的血浆水平平均比口服途径高5倍。虽然血浆浓度仅在短时间内超过了大多数对GEN有反应的人类癌细胞系的IC50值，但药物水平在4小时内保持高于最敏感细胞系的IC50值2μg/ml。单剂量研究的推断表明，每8小时重复腹腔注射至少200mg/kg GEN将使药物持续全身暴露于可能对这些细胞系具有细胞抑制作用的浓度。这些信息应有助于评估GEN在合适的体内肿瘤模型中的有效性。
