, Volume 20, Issue 11, pp 1794-1803

Structural Determinants of P-Glycoprotein-Mediated Transport of Glucocorticoids

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Abstract

Purpose. The aim of this study was to determine requisite structural features for P-glycoprotein-mediated transport of a series of structurally related glucocorticoids (GCs).

Methods. Transport experiments were conducted in wild-type and stably transfected MDR1 LLC-PK cell line. Transport efficiency (Teff = Peff, B→A / Peff, A→B) in both cell lines was compared as a measure of passive diffusion and P-glycoprotein-mediated transepithelial transport for each steroid. Three-dimensional structure-activity relationships were built to determine how specific structural features within the steroids affect their P-gp-mediated efflux.

Results. Mean (± SD) Teff in LLC-PK cells was 1.1 ± 0.17, indicating that differences in structure and partition coefficient did not affect drug flux in the absence of P-glycoprotein. Teff in L-MDR1 cells ranged from 3.6 to 26.6, demonstrating the importance of glucocorticoid structure to P-glycoprotein transport. The rank order of Teff in MDR1 cells was: methylprednisolone> prednisolone > betamethasone > dexamethasone/prednisone > cortisol. There was no correlation between individual Teff values and partition coefficient. 3D-QSAR models were built using CoMFA and CoMSIA with a q2 (r2) of 0.48 (0.99) and 0.41 (0.95), respectively.

Conclusions. Nonpolar bulky substituents around the C-6α position, as well as a hydrogen-bond donor at position C-11, enhance P-glycoprotein affinity and cellular efflux, whereas bulky substituents at C-16 diminish transporter affinity.