The iP-gp cell model is an improved tool for predicting the in vivo relevance of P-gp mediated efflux at the blood-brain barrier

The efflux transporter P-glycoprotein (P-gp, MDR1, ABCB1) is expressed in a number of barrier tissues in the human body, including the luminal membrane of the brain capillary endothelial cells that make up the blood-brain barrier (BBB). P-gp can actively transport a wide range of structurally diverse drug compounds against their concentration gradient, and has a significant impact in limiting brain penetration of a broad range of substrates. P-gp is therefore considered as one of the major obstacles to drug delivery into the central nervous system (CNS). The interaction between P-gp and new drug candidates is investigated in vitro during early states of drug development. It is however uncertain how well the in vitro studies actually predict the in vivo relevant P-gp mediated efflux at the BBB. Recently, we described the development of a MDR1 transfected porcine epithelial cell line (iP-gp), which overexpresses human P-gp, while displaying extremely tight barrier properties comparable to that of a tight BBB, making this cell line a suitable tool for studying human P-gp. The present study aimed at evaluating the applicability of the iP-gp cell line for screening investigational drugs for their susceptibility to P-gp interactions, and how well the cell line could predict the in vivo relevance of P-gp mediated efflux at the BBB in mice. Bidirectional fluxes of 14 drug candidates were measured in iP-gp cells and in MDCK II MDR1 cells, and compared with pharmacokinetic data obtained in male C57BL/6 mice. The iP-gp cells formed markedly tighter cell monolayer (>15 000 Ω∙cm2) than MDCK II MDR1 cells (>250 Ω∙cm2). The Papp in the apical to basolateral (A-B) direction were generally lower in the iP-gp monolayers than in the MDCK II MDR1, indicating a more restrictive paracellular pathway between the iP-gp cells. Both cell models were highly capable of discriminating between compounds with low and high permeation. This was corroborated by Kp,uu from the in vivo studies, where compounds that displayed the lowest Kp,uu in mice generally exhibited the highest efflux ratios and/or lowest Papp,A-B in the two cell models. Thus, the results in the cell models were in good agreement with the in vivo results. 12 compounds displayed a low BBB penetration ability in mice as judged by Kp,uu less than 1, indicating a possible involvement of an efflux transporter or low passive permeability across the BBB. Experimental data from the iP-gp cell model indicated that seven compounds were P-gp substrates, whereas analysis of data from the MDCK II MDR1 cell indicated four compounds were substrates. This suggest the iP-gp cell model may be a more sensitive tool for screening of drug candidates for interaction with human P-gp. Thus, the iP-gp cell line may serve as a useful screening tool in drug development studies.

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