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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.

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References

  1. O. C. Meijer, E. C. de Lange, D. D. Breimer, A. G. de Boer, J. O. Workel, and E. R. de Kloet. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139:1789-1793 (1998).

    Google Scholar 

  2. A. M. Karssen, O. C. Meijer, I. C. van der Sandt, P. J. Lucassen, E. C. de Lange, A. G. de Boer, and E. R. de Kloet. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 142:2686-2694 (2001).

    Google Scholar 

  3. A. Nakayama, O. Eguchi, M. Hatakeyama, H. Saitoh, and M. Takada. Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat small intestine. Biol. Pharm. Bull. 22:535-538 (1999).

    Google Scholar 

  4. S. Bourgeois, D. J. Gruol, R. F. Newby, and F. M. Rajah. Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Mol. Endocrinol. 7:840-851 (1993).

    Google Scholar 

  5. D. J. Gruoland S. Bourgeois. Chemosensitizing steroids: glucocorticoid receptor agonists capable of inhibiting P-glycoprotein function. Cancer Res. 57:720-727 (1997).

    Google Scholar 

  6. K. Ueda, N. Okamura, M. Hirai, Y. Tanigawara, T. Saeki, N. Kioka, T. Komano, and R. Hori. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J. Biol. Chem. 267:24248-24252 (1992).

    Google Scholar 

  7. C. K. van Kalken, H. J. Broxterman, H. M. Pinedo, N. Feller, H. Dekker, J. Lankelma, and G. Giaccone. Cortisol is transported by the multidrug resistance gene product P-glycoprotein. Br. J. Cancer 67:284-289 (1993).

    Google Scholar 

  8. K. M. Barnes, B. Dickstein, G. B. Cutler Jr., T. Fojo, and S. E. Bates. Steroid treatment, accumulation, and antagonism of P-glycoprotein in multidrug-resistant cells. Biochemistry 35:4820-4827 (1996).

    Google Scholar 

  9. A. H. Schinkel, E. Wagenaar, L. van Deemter, C. A. Mol, and P. Borst. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96:1698-1705 (1995).

    Google Scholar 

  10. S. I. Hsu, L. Lothstein, and S. B. Horwitz. Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes. J. Biol. Chem. 264:12053-12062 (1989).

    Google Scholar 

  11. L. Homolya, Z. Hollo, U. A. Germann, I. Pastan, M. M. Gottesman, and B. Sarkadi. Fluorescent cellular indicators are extruded by the multidrug resistance protein. J. Biol. Chem. 268:21493-21496 (1993).

    Google Scholar 

  12. J. M. Ford. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur. J. Cancer 32A:991-1001 (1996).

    Google Scholar 

  13. C. R. Yates, A. Vysokanov, A. Mukherjee, T. M. Ludden, E. Tolley, G. U. Meduri, and J. T. Dalton. Time-variant increase in methylprednisolone clearance in patients with acute respiratory distress syndrome: a population pharmacokinetic study. J. Clin. Pharmacol. 41:415-424 (2001).

    Google Scholar 

  14. Y. C. Martin, M. G. Bures, E. A. Danaher, J. DeLazzer, I. Lico, and P. A. Pavlik. A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists. J. Comput. Aided Mol. Des. 7:83-102 (1993).

    Google Scholar 

  15. R. T. Kroemer, E. Koutsilieri, P. Hecht, K. R. Liedl, P. Riederer, and J. Kornhuber. Quantitative analysis of the structural requirements for blockade of the N-methyl-D-aspartate receptor at the phencyclidine binding site. J. Med. Chem. 41:393-400 (1998).

    Google Scholar 

  16. R. S. Bohacek and C. McMartin. Definition and display of steric, hydrophobic, and hydrogen-bonding properties of ligand binding sites in proteins using Lee and Richards accessible surface: validation of a high-resolution graphical tool for drug design. J. Med. Chem. 35:1671-1684 (1992).

    Google Scholar 

  17. G. Klebe, U. Abraham, and T. Mietzner. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J. Med. Chem. 37:4130-4146 (1994).

    Google Scholar 

  18. M. Torok, H. Gutmann, G. Fricker, and J. Drewe. Sister of P-glycoprotein expression in different tissues. Biochem. Pharmacol. 57:833-835 (1999).

    Google Scholar 

  19. R. J. Raggers, A. van Helvoort, R. Evers, and G. van Meer. The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane. J. Cell Sci. 112(Pt 3):415-422 (1999).

    Google Scholar 

  20. P. Wils, A. Warnery, V. Phung-Ba, S. Legrain, and D. Scherman. High lipophilicity decreases drug transport across intestinal epithelial cells. J. Pharmacol. Exp. Ther. 269:654-658 (1994).

    Google Scholar 

  21. G. H. Rothblat and M. C. Phillips. Mechanism of cholesterol efflux from cells. Effects of acceptor structure and concentration. J. Biol. Chem. 257:4775-4782 (1982).

    Google Scholar 

  22. B. A. Luxonand R. A. Weisiger. A new method for quantitating intracellular transport: application to the thyroid hormone 3,5,3′-triiodothyronine. Am. J. Physiol. 263:G733-G741 (1992).

    Google Scholar 

  23. M. Clarkand R. D. Cramer III. The Probability of Chance Correlation Using Partial Least Squares (PLS). Quant. Struct.Act. Relat. 12:137-145 (1993).

    Google Scholar 

  24. D. J. Gruol, Q. D. Vo, and M. C. Zee. Profound differences in the transport of steroids by two mouse P-glycoproteins. Biochem. Pharmacol. 58:1191-1199 (1999).

    Google Scholar 

  25. S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L. B. Lan, K. Yasuda, R. L. Shepard, M. A. Winter, J. D. Schuetz, J. H. Wikel, and S. A. Wrighton. Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol. Pharmacol. 61:964-973 (2002).

    Google Scholar 

  26. S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L. B. Lan, K. Yasuda, R. L. Shepard, M. A. Winter, J. D. Schuetz, J. H. Wikel, and S. A. Wrighton. Application of three-dimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. Mol. Pharmacol. 61:974-981 (2002).

    Google Scholar 

  27. H. Saitoh, M. Hatakeyama, O. Eguchi, M. Oda, and M. Takada. Involvement of intestinal P-glycoprotein in the restricted absorption of methylprednisolone from rat small intestine. J. Pharm. Sci. 87:73-75 (1998).

    Google Scholar 

  28. K. L. Koszdin, D. D. Shen, and C. M. Bernards. Spinal cord bioavailability of methylprednisolone after intravenous and intrathecal administration: the role of P-glycoprotein. Anesthesiology 92:156-163 (2000).

    Google Scholar 

  29. G. L. Flynn. Structural approach to partitioning: Estimation of steroid partition coefficients based upon molecular constitution. J. Pharm. Sci. 60:345-353 (1971).

    Google Scholar 

  30. A. Leo, C. Hansch, and D. Elkins. Partition coefficients and their uses. Chem. Rev. 71:525-616 (1971).

    Google Scholar 

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Author notes

  1. Cheng Chang & Peter W. Swaan

    Present address: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, 21201

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN, 38163

    Charles R. Yates

  2. Biophysics Program, The Ohio State University, Columbus, OH, 43210

    Cheng Chang, James T. Dalton & Peter W. Swaan

  3. Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, 21201

    Jeffrey D. Kearbey & James T. Dalton

  4. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, 38105

    Kazuto Yasuda & Erin G. Schuetz

  5. Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN, 38163

    Duane D. Miller

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  1. Charles R. Yates
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Correspondence to James T. Dalton.

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Yates, C.R., Chang, C., Kearbey, J.D. et al. Structural Determinants of P-Glycoprotein-Mediated Transport of Glucocorticoids. Pharm Res 20, 1794–1803 (2003). https://doi.org/10.1023/B:PHAM.0000003377.39548.f6

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