Localization of Drug Release Sites from an Oral Sustained‐Release Formulation of 5‐ASA (Pentasa_®) in the Gastrointestinal Tract Using Gamma Scintigraphy

Abstract

Release of 5-ASA from a sustained release formulation (Pentasa, Ferring A/S, Copenhagen, Denmark) was monitored with plasma sampling for up to 24 hours in nine volunteers under both fasted and fed conditions. Drug absorption was correlated with location of the sustained-release microgranules in the gastrointestinal tract by gamma scintigraphy. Disintegration of the labeled tablet preparation occurred in the stomach within 20 minutes and acetylated 5-ASA was detectable in the plasma less than 60 minutes after ingestion. No significant differences were detected in either transit times through the small intestine, peak plasma acetylated 5-ASA concentration or lag time to absorption between fasted and fed individuals. Peak plasma concentration of acetylated 5-ASA usually occurred when the microgranules were present in the small intestine or ascending colon. The pharmacoscintigraphic study confirmed that 5-ASA release from the formulation occurred throughout the gastrointestinal tract, and that food effects on the in vivo behavior of the preparation were minimal.

Mesalazine pharmacokinetics and NAT2 phenotype

“…Because of the short elimination half-life of mesalazine of clearly less than 3 hours [1,7], a prolonged release preparation is needed for maintaining plasma concentrations during a dosing interval, but also for direct delivery to any intestinal site of action. Mesalazine release from this formulation has been reported to occur throughout the gastrointestinal tract [19]. It has a bioavailability of approximately 30 % [18] which is lower than that of gastroresistant tablets and may be in part be caused by a more extensive intestinal first pass metabolism which is saturable [7] (see also Table 1).…”

Predicting Food Effects on Drug Release from Extended-Release Oral Dosage Forms Containing a Narrow Therapeutic Index Drug

“…Mean transit times reported in several gammascintigraphy studies (37)(38)(39)(40)(41)(42) were utilized to simulate fasted-state residence times in the different regions of the GI tract. Further, the different gastric residence times of tablets and small particles (f2 mm) were accounted for in the dissolution model (37,40,42).…”

“…Further, the different gastric residence times of tablets and small particles (f2 mm) were accounted for in the dissolution model (37,40,42). Additionally, to simulate the reuptake of bile acids along the lumen of the small intestine (SI), it was necessary to develop a gradient of bile component concentrations to simulate SI passage adequately.…”

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“…Since fractional absorption in the whole period was as much as 75%, a substantial amount of drug may have been absorbed distally either in the ileum or colon. This discrepancy between visualisation of drug-release, systemic drug concentration measurements and absorption seems to demonstrate the difficulties in defining regional availability of 5-ASA in small intestine from a SR-drug (41,50,51,65,79). Statistical evaluation of data was not reported (79).…”

“…Hence, there is a need to determine the optimal kinetics of a drug in a defined clinical situation as a guide-line for more rational 5-ASAtherapy in the individual patient. Recently, new methods have been reported for the determination of site of release by intestinal isotope-scanning (51,65). Further, the determination of local luminal drug-concentrations by intestinal intubation has been applied (41,69), as well as the determination of tissue-concentrations of the drug (32).…”