Gastrointestinal Behavior of Orally Administered Radiolabeled Erythromycin Pellets in Man as Determined by Gamma Scintigraphy

Abstract

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.

Meal-Induced Acceleration of Tablet Transit Through the Human Small Intestine

“…In a previous paper by our group a similar transit trend was noted; the upper small intestine transit of an enteric coated tablet appeared faster with a pre-feed dose (30 min before food) than that taken after food or on an empty stomach but this was inconclusive since the dosage form was designed to disintegrate in the distal intestine and therefore no relationship could be drawn between the arrival of food and the total small intestinal transit time of the tablet (15). Stronger evidence of a food effect on intestinal transit was noted by Digenis et al (14) who administered enteric coated erythromycin pellets 30 min before food and measured a 50% decrease in bioavailability with this dosing regimen; this was attributed to a more rapid small intestinal transit of the dosage form. This study, however, was complicated by the fact that erythromycin is a prokinetic drug which stimulates gastric and duodenal motility (23).…”

“…Might the arrival of food in the stomach trigger physiological mechanisms in the small intestine which alter the transit of the dosage form? A limited number of previous studies have considered alternative feeding regimens with modified release dosage forms and have reported conflicting effects on transit (14)(15)(16). Here, a study was designed specifically to investigate the timing of food administration on small intestinal transit.…”

Oral modified-release formulations in motion: The relationship between gastrointestinal transit and drug absorption

“…The scintigraphic images showed that in the pre-feed regimen, faster small intestinal transit resulted in disintegration of the enteric beads in the distal regions of the small intestine compared to fasting conditions where drug release occurred in the proximal small intestine. This acceleration may limit absorption of those drugs that are preferably absorbed in the upper gastrointestinal tract (Digenis et al, 1990). This pre-feed acceleration in small intestinal transit and propulsion of the dosage form was explored further by Fadda et al (2009), where gastric emptying of tablets occurred before the arrival of food to the stomach in 60% subjects and small intestinal transit time in those subjects was found to be significantly shorter (100 min) than that observed in the standard fasted (204 min) and fed regimen (210 min).…”

“…There are other scenarios to consider, for example, administration of a multiple-unit formulation 30 min before food (pre-feed regimen) resulted in faster gastric emptying compared to when no food was administered. This suggests that food intake lead to an increase in gastric motility and consequently to a faster gastric emptying (Digenis et al, 1990).…”

Gamma scintigraphy in the evaluation of pharmaceutical dosage forms

“…These problems can be overcome by the incorporation of a non-radioactive tracer with subsequent radiolabelling by neutron activation (Parr et al 1987;Digenis et al 1990;Hardy et al 1991a;Wilding et al 1992c). Two materials, samarium-152 oxide and erbium-170 oxide are commonly used as tracers.…”