Dutta Sandeep, Reed Ronald C, O'Dea Robert F
Clinical Pharmacokinetics, Abbott Laboratories, Abbott Park, IL 60064, USA.
Ann Pharmacother. 2006 Apr;40(4):619-25. doi: 10.1345/aph.1G617. Epub 2006 Mar 28.
The distinct absorption characteristics of the conventional enteric-coated, delayed-release (DR) and the novel extended-release (ER) divalproex sodium formulations are not well recognized.
To quantitatively and qualitatively differentiate the absorption characteristics of divalproex-DR and -ER formulations.
Healthy volunteers (N = 28) received single 1000 mg doses of divalproex-DR and divalproex-ER tablets in a crossover fashion. Noncompartmental and compartmental analyses were used to estimate valproic acid (VPA) pharmacokinetics from the plasma concentration-time profiles determined from intensive blood sampling over 48 hours.
VPA was not absorbed from divalproex-DR in the first 2 hours (absorption lag-time) after dosing. After VPA release in the intestine, approximately 63% of the dose was absorbed in less than 1 hour, that is, 2.9 hours (mean absorption time) from dosing. Maximum concentration (C(max)) was achieved approximately 4 hours after dosing. VPA absorption was complete ( approximately 93% of dose) within 3 absorption half-lives ( approximately 4.5 h) post-absorption lag-time, that is, 6-7 hours from dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, initially at a modest rate, followed by slow and extended absorption at a constant rate for more than 20 hours; VPA concentrations at 1 and 2 hours were 28% and 40% of C(max). Approximately 53% of the dose was absorbed within 12 hours (mean absorption time); complete absorption occurred over more than 20 hours without any dose dumping.
VPA absorption from enteric-coated divalproex-DR is rapid following a lag-time of approximately 2 hours and is complete within 6-7 hours of dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, but occurs at a slow, approximately constant rate over more than 20 hours.
传统肠溶包衣缓释（DR）和新型长效（ER）丙戊酸二钠制剂的独特吸收特性尚未得到充分认识。
定量和定性区分丙戊酸-DR和-ER制剂的吸收特性。
28名健康志愿者以交叉方式单次服用1000mg丙戊酸-DR和丙戊酸-ER片剂。采用非房室和房室分析方法，根据48小时密集采血测定的血浆浓度-时间曲线估算丙戊酸（VPA）的药代动力学。
给药后最初2小时（吸收延迟时间）内，丙戊酸-DR未吸收VPA。VPA在肠道释放后，约63%的剂量在不到1小时内被吸收，即给药后2.9小时（平均吸收时间）。给药后约4小时达到最大浓度（C(max)）。吸收延迟时间后3个吸收半衰期（约4.5小时）内，VPA吸收完成（约93%的剂量），即给药后6-7小时。相比之下，丙戊酸-ER给药后VPA立即开始吸收，最初速率适中，随后以恒定速率缓慢且持续吸收超过20小时；1小时和2小时时的VPA浓度分别为C(max)的28%和40%。约53%的剂量在12小时内被吸收（平均吸收时间）；超过20小时完全吸收，无任何剂量突释。
肠溶包衣丙戊酸-DR给药约2小时延迟后VPA吸收迅速，给药后6-7小时内吸收完成。相比之下，丙戊酸-ER给药后VPA立即开始吸收，但在超过20小时内以缓慢、近似恒定的速率进行。
