title: Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract.
abstract: As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Alex
authors.identifier: 0000-0003-1732-2631
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, College of Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Baker
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Ann F
authors.initials: AF
authors.lastname: Fioritto
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Siwei
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Bly
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsume
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koenigsknecht
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration , Silver Spring, Maryland 20993, United States.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration , Silver Spring, Maryland 20993, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Lionberger
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.affiliation: Department of Internal Medicine, College of Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Hasler
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002626:Chemistry, Pharmaceutical / Q000379:methods; D065546:Drug Liberation / Q000502:physiology*; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D008297:Male; D019804:Mesalamine / Q000378:metabolism*; D008875:Middle Aged; D012995:Solubility; D055815:Young Adult
chemical_list: D019804:Mesalamine
keywords: clinical study; in vivo dissolution; local gastrointestinal concentration; mesalamine; modified release; pharmacokinetics