Gisleskog P O, Hermann D, Hammarlund-Udenaes M, Karlsson M O
Clinical Pharmacology, GlaxoWellcome Research and Development, Middlesex, UK.
Br J Clin Pharmacol. 1999 Jan;47(1):53-8. doi: 10.1046/j.1365-2125.1999.00843.x.
To characterize the pharmacokinetics of the dual 5alpha-reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules.
In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined.
The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half-life increasing with dose. Data were best described by a two-compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h(-1)) combined to give a half-life of up to 5 (1-7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml(-1)), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h(-1), increased and the half-life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV = 70%).
G1198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.
描述双重5α-还原酶抑制剂GI198745（度他雄胺）的药代动力学特征，以便更准确地预测不同给药方案后的GI198745浓度。
在这项随机、单盲、平行组研究中，32名健康男性志愿者单次口服0.01至40mg的GI198745。使用NONMEM通过非线性混合效应模型分析数据，其中检查了线性和非线性药代动力学模型。
GI198745血清浓度的时间过程表明存在浓度依赖性消除，表观半衰期随剂量增加。数据最好用具有一级吸收以及平行线性和非线性消除途径的二室模型来描述。药物吸收迅速，随后是短暂的分布期。高分布容积（511升）和低线性清除率（0.58升/小时）相结合，在高浓度下产生长达5（1 - 7）周的半衰期。随着浓度降至Km（0.96纳克/毫升），通过相对快速的可饱和消除途径消除的比例增加，最大清除率为6.2升/小时，半衰期缩短至约3天。线性清除率的个体间变异性估计较高（CV = 70%）。
具有平行线性和非线性消除的药代动力学模型很好地描述了G1198745的药代动力学。使用该模型的模拟表明，每日剂量为0.1mg时，稳态药物浓度及其达到的速率主要受非线性途径影响，而每日剂量高于1mg时，它们几乎完全受线性途径影响。
