Structural determinants of P-glycoprotein-mediated transport of glucocorticoids.
OBJECTIVE
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 MDRI 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-MDRI 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-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.
Yates
Charles R
CR
Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN 38163, USA.
Chang
Cheng
C
Kearbey
Jeffrey D
JD
Yasuda
Kazuto
K
Schuetz
Erin G
EG
Miller
Duane D
DD
Dalton
James T
JT
Swaan
Peter W
PW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000737:chemistry*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D005938:Glucocorticoids / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D018374:LLC-PK1 Cells; D051379:Mice; D015394:Molecular Structure; D010641:Phenotype; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids