Digenis G A, Sandefer E P, Parr A F, Beihn R, McClain C, Scheinthal B M, Ghebre-Sellassie I, Iyer U, Nesbitt R U, Randinitis E
Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington 40536-0082.
J Clin Pharmacol. 1990 Jul;30(7):621-31. doi: 10.1002/j.1552-4604.1990.tb01865.x.
The behavior of single 250-mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron-activated samarium-153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points. Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 micrograms/mL versus 0.94 micrograms/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0-infinity) of the plasma erythromycin concentration versus time curve, was 7.6 hr/micrograms/mL in the fasted state, versus 3.5 hr/micrograms/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges. Evidence provided by this study: 1) indicates that pellet erosion and absorption of active erythromycin base begins when the enteric-coated pellets reach the highly vascular mucosa of the jejunum and proximal ileum, and is essentially completed within the ileum, with a significant portion absorbed in the medial-to-distal ileum; 2) confirms that acceptable therapeutic plasma levels of erythromycin are attained in nonfasting subjects (Cmax = 0.94 microgram/mL) and that superior plasma erythromycin concentrations (Cmax = 1.64 micrograms/mL) are achieved by administration of the dose on an empty stomach 1 to 2 hours before or after meals; 3) corroborates other comparative studies reporting greater fasting bioavailability with this multiparticulate dosage form of erythromycin base than with reference single tablet or particle-in-tablet formulations; and 4) indicates that neutron activation of stable isotopes incorporated as a normal excipient in industrially-produced formulations provides an effective means for in vivo evaluation of dosage forms through gamma scintigraphy.
在禁食和非禁食条件下，通过γ闪烁扫描法观察了7名男性受试者单次服用250毫克多颗粒剂型红霉素碱（ERYC®）后的行为，每剂包含5个用中子活化钐-153标记的微丸。测定了胃肠道区域内放射性标记微丸的停留时间和位置，并将其与同时刻的红霉素血浆浓度相关联。给药后30分钟进食使禁食状态下的血浆红霉素Cmax和血浆红霉素浓度-时间曲线下面积（AUC）值分别降低了43%和54%。禁食状态下红霉素的平均血浆峰浓度（Cmax）为1.64微克/毫升，而非禁食状态下为0.94微克/毫升。根据血浆红霉素浓度-时间曲线的平均AUC（0至无穷大）确定的口服总生物利用度，禁食状态下为7.6小时/微克/毫升，非禁食状态下为3.5小时/微克/毫升。禁食状态下血浆红霉素浓度达到峰值的平均时间（tmax）为3.3小时，非禁食状态下为2.3小时。禁食和非禁食状态下的红霉素血浆浓度均在可接受的治疗范围内。本研究提供的证据：1）表明肠溶包衣微丸到达空肠和回肠近端高度血管化的粘膜时，活性红霉素碱开始溶蚀和吸收，并在回肠内基本完成，其中很大一部分在回肠中远端被吸收；2）证实非禁食受试者可达到可接受的治疗性血浆红霉素水平（Cmax = 0.94微克/毫升），且在饭前或饭后1至2小时空腹给药可获得更高的血浆红霉素浓度（Cmax = 1.64微克/毫升）；3）证实了其他比较研究的结果，即这种多颗粒剂型的红霉素碱比参比单一片剂或片内颗粒剂型具有更高的禁食生物利用度；4）表明对工业生产制剂中作为常规辅料加入的稳定同位素进行中子活化，为通过γ闪烁扫描法对剂型进行体内评估提供了一种有效手段。
