Heatherington A C, Fisher H L, Sumler M R, Waller C L, Shah P V, Hall L L
Center for Bioengineering, University of Washington, Seattle, Washington, 98195, USA.
Environ Res. 1998 Nov;79(2):138-55. doi: 10.1006/enrs.1998.3862.
The objective of this study was to evaluate the effect of age and dosage on percutaneous absorption and disposition of [14C]chlordecone (Kepone) and to describe results using a physiological based pharmacokinetic (PBPK) model. Female Fischer 344 rats 33 and 82 days old were used as the young and adult animal models, respectively, and were studied over a 10-fold dose range. [14C]Chlordecone (0.286 micromol/cm2) was applied to dorsal skin (2. 3% BSA) and radioactivity was quantified in selected tissues and excreta up to 120 h. Absorption and disposition were also determined at three dose levels up to 2.68 micromol/cm2; fraction absorbed decreased as dose increased. In vitro percutaneous absorption was measured by static and flow-through methods; these yielded similar penetration rates, which were lower than those obtained in vivo. In vivo percutaneous absorption over 120 h was 14.4+/-0.99 and 14.2+/-1. 5% dose in young and adults, respectively. Organ and tissue content increased over time (carcass>liver>kidney), indicating prolonged absorption. Statistical differences between young and old were found for liver, skin, and urine, but not for absorption. Excretion occurred primarily in feces, but also in urine. A biophysically based percutaneous model was fitted to both young and adult in vivo absorption data. This was embedded in a whole body PBPK model which, upon optimization with SAAM II, estimated apparent tissue partition coefficients, urinary and fecal excretion rates, and parameters characterizing hepatic nonlinear uptake of bound chlordecone. The model reasonably predicted tissue chlordecone content at higher doses, when decreased absorption was accounted for.
本研究的目的是评估年龄和剂量对[14C]开蓬（十氯酮）经皮吸收和处置的影响，并使用基于生理的药代动力学（PBPK）模型描述结果。分别将33日龄和82日龄的雌性Fischer 344大鼠用作幼年和成年动物模型，并在10倍剂量范围内进行研究。将[14C]开蓬（0.286微摩尔/平方厘米）涂抹于背部皮肤（2.3%体表面积），并在长达120小时的时间内对选定组织和排泄物中的放射性进行定量。在高达2.68微摩尔/平方厘米的三个剂量水平下也测定了吸收和处置情况；吸收分数随剂量增加而降低。通过静态和流通法测量体外经皮吸收；这些方法产生的渗透速率相似，均低于体内获得的速率。在幼年和成年大鼠中，120小时内的体内经皮吸收分别为剂量的14.4±0.99%和14.2±1.5%。器官和组织含量随时间增加（ carcass>肝脏>肾脏），表明吸收时间延长。在肝脏、皮肤和尿液中发现了幼年和成年大鼠之间的统计学差异，但在吸收方面未发现差异。排泄主要发生在粪便中，但也发生在尿液中。将基于生物物理学的经皮模型与幼年和成年大鼠的体内吸收数据进行拟合。将其嵌入全身PBPK模型中，该模型在使用SAAM II进行优化后，估计了表观组织分配系数、尿液和粪便排泄率以及表征肝脏对结合开蓬非线性摄取的参数。当考虑到吸收减少时，该模型合理地预测了较高剂量下组织中开蓬的含量。
