title: Do the recommended standards for in vitro biopharmaceutic classification of drug permeability meet the "passive transport" criterion for biowaivers?
abstract: BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion. Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be used as standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosalto- mucosal) through the rat small intestine revealed significant active transport for four out of the nine high-permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetry was abolished at 4°C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4°C compared to standard conditions (37°C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards. The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia. simon.zakelj@ffa.uni-lj.si
authors.forename: Simon
authors.initials: S
authors.lastname: Žakelj
authors.forename: Katja
authors.initials: K
authors.lastname: Berginc
authors.forename: Robert
authors.initials: R
authors.lastname: Roškar
authors.forename: Bor
authors.initials: B
authors.lastname: Kraljič
authors.forename: Albin
authors.initials: A
authors.lastname: Kristl
mesh_terms: D000818:Animals; D001692:Biological Transport; D001702:Biopharmaceutics / Q000592:standards; D018938:Caco-2 Cells; D017408:Guidelines as Topic; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000145:classification* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D004364:Pharmaceutical Preparations