Abstract
Purpose. In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions.
Methods. P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 μM.
Results. Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 ∼25-50 μM) but SVA not showing any inhibition of P-gp.
Conclusions. The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.
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REFERENCES
T. R. Pedersen, K. Berg, and T. J. Cook. et. al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Survival Study. Arch. Intern. Med. 156:2085-2092 (1996).
R. F. Reinoso, A. Sanchez Navarro, M. J. Garcia, and J. R. Prous. Pharmacokinetic interactions of Statins. Methods Find Exp. Clin. Pharamacol. 23:541-566 (2001).
M. Igel, T. Sudhop, and K. vonBergman. Metabolism and drug interactions of 3-hydroxy-3methylglutaryl coenzyme A-reductase inhibitors (statins). Eur. J. Clin. Pharmacol. 57:357-364 (2001).
P. D. Thompson, P. Clarkson, and R. H. Karas. Statin Associated Myopathy. JAMA 289:1681-1690 (2003).
T. Prueksaritanont, B. Ma, and C. Tang. et. al. Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations. Br. J. Clin. Pharmacol. 47:291-298 (1999).
T. Prueksaritanont, C. Tang, Y. Qui, L. Mu, R. Subramanian, and J. H. Lin. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos. 839:1280-1287 (2002).
P. H. Siedlik, S. C. Olson, B. B. Yang, and R. H. Stern. Erythromycin coadministration increases plasma atorvastatin concentrations. J. Clin. Pharmacol. 39:501-504 (1999).
E. Wang, C. N. Casciano, R. P. Clement, and W. W. Johnson. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm. Res. 18:800-806 (2001).
K. Bogman, A.-K. Peyer, M. Torok, E. Kusters, and J. Drewe. HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br. J. Pharmacol. 132:1183-1192 (2001).
T. Sakaeda, K. Takara, and M. Kakumoto. et. al. Simvastatin and lovastatin, but not pravastatin, interact with MDR1. J. Pharm. Pharmacol. 54:419-423 (2002).
A. H. Schinkel. The physiological function of drug-transporting P-glycoproteins. Semin. Cancer Biol. 8:161-170 (1997).
Z. C. Gatmaitan and I. M. Arias. Structure and function of P-glycoprotein in normal liver and small intestine. Adv. Pharamcol 24:77-97 (1993).
F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and cross-reactivity of one antibody with a muscle protein. J. Histochem. Cytochem. 37:159-164 (1989).
C. Cordon-Cardo. O'brien JP, Boccia J, Casals D, Bertino JR, and Melamed MR Expression of multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem. 38:1277-1287 (1990).
X. Wu, L. R. Whitfeild, and B. H. Stewart. Atorvastatin transport in Caco-2 cell model: Contribution of P-glycoprotein and Proton-monocarboxylic acid transporter. Pharm. Res. 17:209-215 (2000).
M. Yamazaki, W. E. Neway, and T. Ohe. Chen I-Wu, Rowe JF, Hochman JH, Chiba M, and Lin JH. In vitro substrate identification studies for P-glycoprotein-mediated transport: Species difference and predictability of in vivo results. J. Pharamacol. Exp. Ther. 296:723-735 (2001).
D. W. Shen, C. Cardarelli, J. Hwang, M. Cornwell, N. Richert, S. Ishii, I. Pastan, and M. M. Gottesman. Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J. Biol. Chem. 26bd1:7762-7770 (1986).
A. H. Schinkel, E. Wagenaar, L. VanDeemter, C. A. A. M. Mol, and P. Borst. Absence of mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone digoxin and cyclosporin A. J. Clin. Invest. 96:1698-1705 (1995).
H. Lennernas. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet. 42:1141-1160 (2003).
J. W. Polli, S. A. Wring, J. E. Humphreys, L. Huang, J. B. Morgan, L. O. Webster, and C. S. Serabjit-Singh. Rational use of P-glycoprotein assays in drug discovery. J. Pharmacol. Exp. Ther. 299:620-628 (2001).
S. Scala, N. Akhmed, U. S. Rao, K. Paull, L. B. Lan, B. Dickstein, J. S. Lee, G. H. Elgemeie, W. D. Stein, and S. E. Bates. P-glycoprotein substrates and antagonists cluster into two distinct groups. Mol. Pharmacol. 51:1024-1033 (1997).
Zocor product insert. Physicians Desk Reference 56th edition. 2002; 2219-2223.
J. V. Asperen, O. van Tellingen, A. H. Schinkel, and J. H. Beijnen. Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild-type and mice lacking mdr1a P-glycoprotein. J. Pharmacol. And Exp. Therap. 289:329-333 (1999).
R. B. Kim, M. F. Fromm, C. Wandel, B. Leake, A. J. J. Wood, D. M. Roden and G. R. Wilkinson. The drug transporter P-glycoprotein limits oral absorption and brain entry of of HIV-1 protease inhbitors. J. Clin. Invest. 101:289-294 (1998).
A. H. Schinkel, E. Wagenaar, C. A. Mol, and L. van Deemter. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517-2524 (1996).
D. Nakai, R. Nakagomi, Y. Furuta, T. Tokui, T. Abe, T. Ikeda, and K. Nishimura. Human liver specific anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Therap. 297:861-867 (2001).
K. Nezasa, K. Higaki, M. Takeuchi, M. Nakano, and M. Koike. Uptake of rosuvastatin by isolated rat hepatocytes: comparison with pravastatin. Xenobiotica 33:379-388 (2003).
Y. Shitara, T. Itoh, H. Sato, A. P. Li, and Y. Sugiyama. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J. Pharmacol. Exp. Ther. 304:610-616 (2003).
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Hochman, J.H., Pudvah, N., Qiu, J. et al. Interactions of Human P-glycoprotein with Simvastatin, Simvastatin Acid, and Atorvastatin. Pharm Res 21, 1686–1691 (2004). https://doi.org/10.1023/B:PHAM.0000041466.84653.8c
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DOI: https://doi.org/10.1023/B:PHAM.0000041466.84653.8c