Chen Cuiping, Cowles Verne E, Sweeney Michael
Depomed Inc., 1360 O'Brien Drive, Menlo Park, CA 94025, USA.
Curr Clin Pharmacol. 2013 Feb 1;8(1):67-72.
Gabapentin is approved for the treatment of postherpetic neuralgia (PHN) and epilepsy. The pharmacokinetic (PK) properties of gabapentin, including absorption, distribution, metabolism, and excretion (ADME), were investigated during the development of Neurontin®, an immediate-release (IR) formulation of gabapentin that is orally administered three-times daily. Recently, a gastroretentive (GR) once-daily formulation of gabapentin (Gralise®) has been developed and marketed for the treatment of PHN. This review focuses on the ADME properties of gabapentin and illustrates how GR delivery enhances its absorption compared with IR formulations and allows once-daily dosing with the evening meal for the treatment of PHN. It includes the following aspects: 1) the mechanism of gastroretention of gabapentin GR tablets, 2) in vitro dissolution profiles of the GR and IR formulations, 3) site of absorption of gabapentin in the human intestine, 4) studies of the mechanism of gabapentin absorption using intestinal tissue preparations, 5) human PK studies to examine the effects of dose and formulations on PK profiles and the bioavailability of gabapentin at therapeutically relevant doses, and 6) efficacy and safety of gastroretentive gabapentin in patients with PHN. The data reviewed support that GR delivery of gabapentin optimizes its absorption via a saturable uptake mechanism. The prolonged residence of the GR tablets in the stomach coupled with the gradual release of gabapentin attenuates saturation of the transporter, thus enhancing absorption and increasing bioavailability, especially at therapeutically relevant doses. The net result is a once-daily formulation of gabapentin that is well tolerated and efficacious for the treatment of PHN.
加巴喷丁被批准用于治疗带状疱疹后神经痛（PHN）和癫痫。在Neurontin®（加巴喷丁的速释（IR）制剂，每日口服三次）的研发过程中，对加巴喷丁的药代动力学（PK）特性，包括吸收、分布、代谢和排泄（ADME）进行了研究。最近，一种胃滞留（GR）的加巴喷丁每日一次制剂（Gralise®）已被开发并上市用于治疗PHN。本综述重点关注加巴喷丁的ADME特性，并说明与IR制剂相比，GR给药如何增强其吸收，并允许在晚餐时每日一次给药来治疗PHN。它包括以下几个方面：1）加巴喷丁GR片的胃滞留机制；2）GR和IR制剂的体外溶出曲线；3）加巴喷丁在人体肠道中的吸收部位；4）使用肠道组织制剂对加巴喷丁吸收机制的研究；5）人体PK研究，以检查剂量和制剂对PK曲线的影响以及加巴喷丁在治疗相关剂量下的生物利用度；6）胃滞留型加巴喷丁在PHN患者中的疗效和安全性。所综述的数据支持加巴喷丁的GR给药通过可饱和摄取机制优化其吸收。GR片在胃中的长时间停留以及加巴喷丁的逐渐释放减弱了转运体的饱和，从而增强吸收并提高生物利用度，特别是在治疗相关剂量下。最终结果是一种加巴喷丁每日一次制剂，对PHN的治疗耐受性良好且有效。
