P-glycoprotein, an ATP-dependent efflux pump, is a membrane transporter that influences the absorption and excretion of drugs. There is a striking overlap between the substrates for CYP3A4 and P-glycoprotein. This study was designed to assess whether udenafil, a substrate of CYP3A4, is also a P-glycoprotein substrate. Udenafil stimulated P-glycoprotein ATPase activity, a putative measure of P-glycoprotein affinity, although with lower affinity than a proven substrate, verapamil. Bidirectional transport studies of udenafil using Caco-2 cell monolayers showed that its efflux (15.9-22.8 x 106 cm/s) was significantly higher than its influx (3.7-9.1 × 106 m/s). P-glycoprotein inhibitors such as cyclosporine, tariquidar and verapamil significantly increased the influx of udenafil and decreased the efflux of udenafil. These results indicate that udenafil is a substrate for P-glycoprotein. The low bioavailability, variable absorption and drug-drug interactions of udenafil may be related to the variability of CYP3A4 and P-glycoprotein expression and to possible CYP3A4 and P-glycoprotein interactions.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I., and Gottesman, M. M., Biochemical, cellular and pharmacological aspects of the multidrug transporter.Ann. Rev. Pharmacol. Toxicol., 39, 361–398 (1999).
Ahn, B. O., Kang, K. K., Ahn, G. J., Kwon, J. W., Kim, W. B., Kang, K. S., and Lee, Y. S., Efficacy of DA-8159, a new PDE5 inhibitor, for inducing penile erection in rabbits with acute spinal cord injury.Int. J. Impot. Res., 15, 405–411 (2003).
Benet, L. Z. and Cummins, C. L., The drug efflux-metabolism alliance: biochemical aspects.Adv. Drug Del. Rev., 50, S3-S11 (2001).
Choi, S. J., Ji, H. Y., Lee, H. Y., Kim, D. S., Kim, W. B., and Lee, H. S., In vitro metabolism of a novel phosphodiesterase-5 inhibitor DA-8159 in rat liver preparations using liquid chromatography/electrospray mass spectrometry.Biomed. Chromatogr., 16, 395–399 (2002).
Drueckes, P., Schinzel, R., and Palm, D., Photometric microtiter assay of inorganic phosphate in the presence of acid-labile organic phosphates.Anal. Biochem., 230, 173–177 (1995).
Gan, L. L., Moseley, M. A., Khosla, B., Augustijns, P. F., Bradshaw, T. P., Hendren, R. W., and Thakker, D. R., CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells: Interaction between the two biochemical barriers to intestinal transport.Drug Metab. Dispos., 24, 344–349 (1996).
Gres, M. C., Julian, B., Bourne, M., Meunier, V., Roques, C., Berger, M., Boulenc, X., Berger, Y., and Fabre, G., Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line.Pharm. Res., 15, 726–733 (1998).
Hidalgo, I. J., Assessing the absorption of new Pharmaceuticals.Current Topics Med. Chem., 1, 385–401 (2001).
Hoffmeyer, S., Burk, O., Von Richter, O., Arnold, H. P., Brockmoller, J., Johne, A., Cascorli, I., Gerloff, T., Roots, I., Eichelbaume, M., and Brinkmann, U., Functional polymorphism of the human multidrug-resistant gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activityin vivo.Proc. Natl. Acad. Sci., 97, 4373–4378 (2000).
Hunter, J., Hirst, B. H., and Simmons, N. L., Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers.Pharm. Res., 10, 743–749 (1993).
Ji, H. Y., Lee, H. W., Kim, H. H., Kim, D. S., Yoo, M., Kim, W. B., and Lee, H. S., Role of human Cytochrome P450 3A4 in the metabolism of DA-8159, a new erectogenic.Xenobiotica, 34, 973–982 (2004).
Kang, K. K., Yu, J. Y., Yoo, M., and Kwon, J. W., The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction.Int. J. Impot. Res., 17, 409–416 (2005).
Kim, J., Kim, S. J., Ji, H. Y., Jin, J. K., Lee, S. S., Kim, D. S., Yoo, M., Kim, W. B., and Lee, H. S., Simultaneous determination of a new phosphodiesterase-5 inhibitor DA-8159 and its active metabolite in human plasma by high performance liquid chromatography with tandem mass spectrometry.Chromatographia, 57, 447–450 (2003).
Kim, H. H., Ji, H. Y., Lee, H. Y., Kim S. A., Lee, S., Yi, K. Y., and Lee, H. S., Characterization of cytochrome P450 enzymes and P-glycoprotein involved in the metabolism and transport of a new anti-angiogenic agent KR-31831.Drug Devel. Res., 66, 40–49 (2006).
Martin, C., Berridge, G., Mistry, P., Higgins, C., Charlton, P., and Callaghan, R., The molecular interaction of the affinity reversal agent XR9576 with P-glycoprotein.Br. J. Pharmacol., 128, 403–411 (1999).
Meunier, V., Bourne, M., Berger, Y., and Fabre, G., The human intestinal epithelial cell line Caco-2: pharmacological and pharmacokinetic applications.Cell. Biol. Toxicol., 11, 187–194 (1995).
Oh, T. Y., Kang, K. K., Ahn, B. O., Yoo, M., and Kim, W. B., Erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159.Arch. Pharm. Res., 23, 471–476 (2000).
Sarkardi, B, Price, E. M., Boucher, R. C., Germann, U. A., and Scarborough, G. A., Expression of the human multidrug resistance cDNA in insect cells generates a high-activity drug-stimulated membrane ATPase.J. Biol. Chem., 267, 4854–4858 (1992).
Schmiedlin-Ren, P., Thummel, K. E., Fisher, J. M., Paine, M. F., Lown, K. S., and Watkins, P. B., Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1 a,25- dihydroxyvitamin D3.Mol. Pharmacol., 51, 741–754 (1997).
Shim, H. J., Kim, Y. C., Park, K. J., Kim, D. S., Kwon, J. W., Kim, W. B., and Lee, M. G., Pharmacokinetics of DA-8159, a new erectogenic, after intravenous and oral administration to rats: hepatic and intestinal first-pass effects.J. Pharm. Sci., 28, 2185–2195 (2003).
Silverman, J. A., P-Glycoprotein. In: Levi, R. H., Thummel, K. E., Trager, W. F., Hansten, P. D., Eichelbaum, M., editors. Metabolic Drug Interactions. Philadelpia, Lippincott Williams & Wilkins. p 135–144 (2000).
Wacher, V. J., Wu, C. Y., and Benet, L. Z., Overlapping substrate specificities and tissue distribution of cytochrme P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy.Mol. Carcinog., 13, 129–134 (1995).
Wacher, V. J., Salphati, L., and Benet, L. Z., Active secretion and enterocytic drug metabolism barriers to drug absorption.Adv. Drug Deliv. Rev., 46, 89–102 (2001).
Walle, U. K. and Walle, T., Taxol transport by human intestinal epithelial Caco-2 cells.Drug Metab. Dispos., 26, 343–346 (1998).
Williams, W. C. and Sinko, P. J., Oral absorption of the HIV protease inhibitors: a current update.Adv. Drug Deliv. Rev., 39, 211–238 (1999).
About this article
Cite this article
Ji, H.Y., Shim, H.J., Yoo, M. et al. Transport of a new erectogenic udenafil in caco-2 cells. Arch Pharm Res 30, 1168 (2007). https://doi.org/10.1007/BF02980254