Structural determinants of P-glycoprotein-mediated transport of glucocorticoids

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 (T-eff = P-eff, (B-->A) / P-eff, (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) T-eff 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. T-eff 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 T-eff 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 q(2) (r(2)) of 0.48 (0.99) and 0.41 (0.95), respectively. Conclusions. Nonpolar bulky substituents around the C-6alpha 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.