title: Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.
abstract: The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) < 50%). There was a clear correlation between in vitro Caco-2 permeability and Frel(colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.
authors.affiliation: AstraZeneca, R&D Sodertalje, Sodertalje, Sweden. Christer.Tannergren@AstraZeneca.com
authors.forename: Christer
authors.initials: C
authors.lastname: Tannergren
authors.forename: Anna
authors.initials: A
authors.lastname: Bergendal
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
authors.forename: Bertil
authors.initials: B
authors.lastname: Abrahamsson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018938:Caco-2 Cells; D003106:Colon / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D004364:Pharmaceutical Preparations / Q000145:classification* / Q000378:metabolism*; D012995:Solubility; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations