Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka, Japan.
Biol Pharm Bull. 2011;34(11):1731-6. doi: 10.1248/bpb.34.1731.
The purpose of this study was to investigate the pharmacokinetics of nilvadipine (NiD) from disintegration-controlled matrix tablets (DCMT). A further purpose was to clarify biological factors that affect the absorption of NiD from DCMT. Two DCMT formulations, which released approximately 80% of NiD in 6 h (DCMT-M) and 10 h (DCMT-S) in vitro, were prepared and compared with immediate-release (IR) tablets. The T(max) and mean residence time from DCMT-M and DCMT-S were significantly longer than those from IR tablets in fasted dogs. The area under the plasma concentration-time curve (AUC) (0-infinity) from DCMT-M in both fed and fasted dogs and IR tablets were comparable in both fed and fasted dogs, indicating complete drug release and absorption without food effect. In contrast, the AUC from DCMT-S was significantly lower than the AUC from IR tablets in fasted dogs. The AUC from DCMT-S increased in fed dogs, but it was still lower than the AUC from IR tablets. In vivo absorption profiles calculated by deconvolution method suggested that the duration of drug absorption from DCMT-S was prolonged from 6 h in fasted condition to 8 h in fed condition, suggesting longer gastro-intestinal (GI) transit time in fed condition allowed longer drug release duration from DCMT-S. Regional drug absorption was also evaluated using NiD solution. The results indicated NiD was almost completely absorbed from canine jejunum, ileum and colon, indicating drug permeation is not a rate-limiting factor of NiD absorption. Therefore, limited GI transit time is the primary factor that affects the drug release from DCMT and subsequent NiD absorption.
本研究旨在考察硝苯地平（NiD）从崩解控制型基质片（DCMT）中释放的药代动力学，并阐明影响 NiD 从 DCMT 吸收的生物学因素。制备了两种体外大约 6 小时（DCMT-M）和 10 小时（DCMT-S）释放 80%NiD 的 DCMT 制剂，并与即刻释放（IR）片进行比较。在禁食犬中，DCMT-M 和 DCMT-S 的 T(max)和平均驻留时间明显长于 IR 片。在禁食和进食犬中，DCMT-M 的 AUC（0-无穷大）与 IR 片在进食和禁食犬中均具有可比性，表明无食物效应时完全释放和吸收药物。相比之下，DCMT-S 的 AUC 在禁食犬中明显低于 IR 片。在进食犬中，DCMT-S 的 AUC 增加，但仍低于 IR 片。反卷积法计算的体内吸收曲线表明，DCMT-S 的药物吸收时间从禁食状态的 6 小时延长至进食状态的 8 小时，提示进食状态下更长的胃肠道（GI）转运时间允许 DCMT-S 释放更长的药物持续时间。还使用 NiD 溶液评估了区域药物吸收。结果表明，NiD 几乎完全从犬空肠、回肠和结肠吸收，表明药物渗透不是 NiD 吸收的限速因素。因此，有限的 GI 转运时间是影响 DCMT 药物释放和随后 NiD 吸收的主要因素。
