title: Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration.
abstract: Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.
authors.affiliation: Amylin Pharmaceuticals, Inc. 9360 Towne Centre Dr, Ste 110, San Diego, CA 92121, United States.
authors.forename: Bronislava R
authors.initials: BR
authors.lastname: Gedulin
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Smith
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Jodka
authors.forename: Kim
authors.initials: K
authors.lastname: Chen
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhavsar
authors.forename: Loretta L
authors.initials: LL
authors.lastname: Nielsen
authors.forename: David G
authors.initials: DG
authors.lastname: Parkes
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Young
mesh_terms: D000336:Aerosols; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004333:Drug Administration Routes; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000336:Aerosols; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide