Journal
MOLECULAR PHARMACEUTICS
Volume 6, Issue 1, Pages 11-18Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp800122b
Keywords
In vitro; MDCKII-MDR1; BCS; BDDCS; passive permeability; biopharmaceutics classification system; intestinal absorption; Caco-2; P-glycoprotein; transporter
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The Biopharmaceutics Classification System(BCS) is the so entific basis for classifying drugs based on their aqueous solubility and intestinal permeability that supports in vivo bioavailability and bioequivalence waivers for immediate-release solid dosage form drugs. One requirement of the BCS is that the permeability method must be validated. In order to accommodate the variety of in vitro/in situ permeability models, the BCS Guidance gives a general framework for the validation requirements, necessitating implemented experimental details to be selected by the applicant laboratory. The objective of this work was to define the parameters for a cell based in vitro permeability method (e.g., cell type, pH, transport direction, tine, and concentration) and validate the method to support formal BCS classification of drugs. Twenty reference c rugs wee selected and permeability values determined using the Madin-Darby canine kidney type II call line heterologously expressing the human P-glycoprotein transporter (MDCKII-MDR). A rank order relationship was established between the in vitro permeability value and human intestinal absorption values. This relationship was as predicted and validates the MDCKII-MDR1 permeability method as defined by the BCS Guidance. The final validated in vitro permeability method employs the MDCKI-MDR1 cell line incubated wit) the Pgp inhibitor GF120918. It is a unidirectional epic to base alter transport assay performed at apical pH values of 5.5 and 7.4 and a basolateral: pH of 7.4. Four reference standards, (metoprolol, pindolol:, labetalol and ranitidine) dosed and analyzed as a single cassette are included in each experiment. A strategy on selection of drug concentrations and on iron to deal with problematic compounds (i.e., those suffering from poor mass balance; is discussed.
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