title: Intestinal permeability and excretion into bile control the arrival of amlodipine into the systemic circulation after oral administration.
abstract: The objective of this study was to identify the factors controlling the arrival of amlodipine into the systemic circulation after oral administration in the fasting state. Dissolution data were collected with the rotating paddle and the flow-through apparatus. Caco-2 cell lines were used to assess the intestinal permeability characteristics. Actual in-vivo data were collected in 24 fasted healthy subjects after single-dose administration of the same amlodipine besylate tablet formulation used in the in-vitro dissolution studies. Regardless of the hydrodynamics, dissolution of amlodipine besylate tablets was rapid and complete in media simulating the contents of the upper gastrointestinal tract in the fasting state. Permeability of amlodipine through Caco-2 cell lines was lower than propranolol's and higher than ranitidine's, indicating that transport through the intestinal mucosa may be one process that limits the arrival into the systemic circulation. Indeed, the de-convoluted profile indicated that arrival into portal blood occurs at rates much slower than gastric emptying or dissolution rates. However, prediction of amlodipine's mean plasma profile after oral administration became possible only after additionally assuming excretion of amlodipine into the bile and a reasonable gastrointestinal residence time. Interestingly, in-vitro permeability data collected in this or in previous studies were inappropriate for simulating the mean actual plasma profile.
authors.affiliation: PLIVA Research and Development Ltd., Prilaz baruna Filipovića 29, 10 000 Zagreb, Croatia.
authors.forename: Dragica
authors.initials: D
authors.lastname: Rausl
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Fotaki
authors.forename: Ruzica
authors.initials: R
authors.lastname: Zanoski
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.forename: Biserka
authors.initials: B
authors.lastname: Cetina-Cizmek
authors.forename: M Zahirul I
authors.initials: MZ
authors.lastname: Khan
authors.forename: Christos
authors.initials: C
authors.lastname: Reppas
mesh_terms: D000284:Administration, Oral; D000328:Adult; D017311:Amlodipine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D008567:Membranes, Artificial; D010539:Permeability; D012995:Solubility
chemical_list: D002121:Calcium Channel Blockers; D008567:Membranes, Artificial; D017311:Amlodipine