Janning P, Schuhmacher U S, Upmeier A, Diel P, Michna H, Degen G H, Bolt H M
Institut für Arbeitsphysiologie an der Universität Dortmund, Germany.
Arch Toxicol. 2000 Oct;74(8):421-30. doi: 10.1007/s002040000149.
Female DA/Han rats were given the phytoestrogen daidzein, either intravenously (10 mg/kg b.w.) or orally by gavage (10 or 100 mg/kg b.w.). The plasma concentration-time curve determined after i.v. administration of daidzein was fitted to a triexponential model, resulting in a final half-life (gamma-phase) of approximately 4 h. The oral bioavailability of 10 mg daidzein/kg was 9.7%, while that of 100 mg/kg was 2.2%; the higher dose (100 mg/kg) was apparently absorbed to a four- to fivefold lower extent than the smaller dose. The plasma concentration time curves after oral administration of daidzein to female DA/Han rats revealed pronounced interindividual differences and multiple peaks, pointing to extensive enterohepatic circulation and/or protracted absorption from the gastrointestinal tract. As shown in a separate experiment with bile duct-cannulated rats, daidzein (i.p. 10 mg/kg b.w.) is efficiently excreted with bile: glucuronide/sulfate metabolites amounting to approximately 30% of the dose in 8 h. Conjugates were also the main circulating metabolites upon i.v. or gavage administration of daidzein, indicating efficient phase II metabolism in female DA/Han rats. Since only few data have been published on tissue levels of isoflavones, their concentrations were measured in various organs and compared to plasma levels determined at the time the animals were killed, with one exception 32 or 48 h after rats had received a single dose of daidzein (i.v. or per os). As expected, the daidzein concentrations depended upon dose and administration route. Despite notable differences in the absolute amounts of total daidzein (free plus hydrolyzed conjugates), the levels were usually three- to fivefold higher in liver and kidney than in plasma; in most samples of uteri, the concentrations were similar, or up to twofold higher, than the respective plasma levels. These data point to an uptake and storage of isoflavones and metabolites in tissues. Experimental toxicokinetics appear to be a relevant subject that should be integrated into assessments of toxicological data for endocrine modulators.
对雌性DA/Han大鼠静脉注射（10毫克/千克体重）或灌胃给予（10或100毫克/千克体重）植物雌激素大豆苷元。静脉注射大豆苷元后测定的血浆浓度-时间曲线拟合为三指数模型，最终半衰期（γ相）约为4小时。10毫克大豆苷元/千克的口服生物利用度为9.7%，而100毫克/千克的口服生物利用度为2.2%；较高剂量（100毫克/千克）的吸收程度明显比小剂量低四到五倍。对雌性DA/Han大鼠口服大豆苷元后的血浆浓度时间曲线显示出明显的个体间差异和多个峰值，表明存在广泛的肠肝循环和/或胃肠道的持续吸收。在一项对胆管插管大鼠的单独实验中表明，大豆苷元（腹腔注射10毫克/千克体重）可有效随胆汁排泄：8小时内葡糖醛酸/硫酸盐代谢物约占剂量的30%。静脉注射或灌胃给予大豆苷元后，结合物也是主要的循环代谢物，表明雌性DA/Han大鼠存在有效的Ⅱ相代谢。由于关于异黄酮组织水平的公开数据很少，在大鼠单次给予大豆苷元（静脉注射或口服）32或48小时后（有一个例外），测定了其在各种器官中的浓度，并与处死动物时测定的血浆水平进行比较。正如预期那样，大豆苷元浓度取决于剂量和给药途径。尽管总大豆苷元（游离加水解结合物）的绝对量存在显著差异，但肝脏和肾脏中的水平通常比血浆高3至5倍；在大多数子宫样本中，浓度与相应血浆水平相似，或高出两倍。这些数据表明异黄酮及其代谢物在组织中有摄取和储存。实验毒代动力学似乎是一个相关主题，应纳入内分泌调节剂毒理学数据的评估中。
