Permeation of losartan across human respiratory epithelium: An in vitro study with Calu-3 cells

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Permeation of losartan across human respiratory epithelium: An in vitro study with Calu-3 cells

The potential for nasal delivery of losartan, a drug with poor oral bioavailability, was investigated using Calu-3 cells. Epithelial permeation of the drug with or without dimethyl-β-cyclodextrin (DM-β-CD) and glycocholate was investigated. Possible transport mechanism of the compound and epithelial mucosal tolerance were screened. Reversibility of epithelial membrane perturbation was also investigated by measuring transepithelial electrical resistance (TEER) recovery over a 24-h period following drug formulation exposure. The permeability coefficient of losartan was 1.3 ± 0.5 × 10-6 cm s-1. This flux was not significantly different from that of formulations containing DM-β-CD (0.5 and 1.0%) or glycocholate (0.5%). However, the formulation with 1.0% glycocholate significantly increased losartan permeation 7-fold. Losartan flux across the cells was concentration-dependent. Serosal to mucosal permeation was significantly higher than mucosal to serosal permeation. Concentration-dependency, as well as polarity in transport indicated that the flux of the compound across Calu-3 cells was not limited to passive diffusion. Cells exposed to DM-&bT-CD (0.5 and 1.0%) and glycocholate (0.5%) caused no significant change in TEER and mitochondrial dehydrogenase activity (MDH). The results of the study showed that losartan may be a suitable drug candidate for nasal delivery.

F. He and G. MacGregor, Salt, blood pressure and cardiovascular disease, Curr. Opin. Cardiol. 22 (2007) 298-305; DOI: 10.1097/HCO.0b013e32814f1d8c.

R. Hernandez-Hernandez, B. Sosa-Canache, M. Velasco, M. J. Armas-Hernandez, M. C. Armas-Padilla and R. Cammarata, Angiotensin II receptor antagonists role in arterial hypertension, J. Hum. Hypertens. 16 (2002) S93-99; DOI: 10.1038/sj/jhh/1001352.

M. W. Lo, M. R. Goldberg, J. B. McCrea, H. Lu, C. I. Furtek and T. D. Bjornsson, Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans, Clin. Pharmacol. Ther. 58 (1995) 641-649; DOI: 10.1016/0009-9236(95)90020-9.

H. R. Costantino, L. Illum, G. Brandt, P. H. Johnson and S. C. Quay, Intranasal delivery: physicochemical and therapeutic aspects, Int. J. Pharm. 337 (2007) 1-24; DOI: 10.1016/j.ijpharm.2007.03.025.

M. I. Ugwoke, R. U. Agu, N. Verbeke and R. Kinget, Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives, Adv. Drug Deliv. Rev. 57 (2005) 1640-1665, DOI: 10.1016/j.addr.2005.07.009.

R. Agu and M. Ugwoke, In Situ and Ex Vivo Nasal Models for Preclinical Drug Development Studies, in Drug Absorption Studies in Situ, in Vivo and In Silico Models (Eds. C. Ehrhardt and K. Kim), AAPS Pharmaceutical Press, New York 2008, pp. 112-134; DOI: 10.1007/978-0-387-74901-3_5.

T. Yang, A. Hussain, J. Paulson, T. J. Abbruscato and F. Ahsan, Cyclodextrins in nasal delivery of low-molecular-weight heparins: in vivo and in vitro studies, Pharm. Res. 21 (2004) 1127-1136; DOI: 10.1023/B:PHAM.0000032998.84488.7a.

T. Seki, H. Kanbayashi, S. Chono, Y. Tabata and K. Morimoto, Effects of a sperminated gelatin on the nasal absorption of insulin, Int. J. Pharm. 338 (2007) 213-218; DOI: 10.1016/j.ijpharm.2007.02.004.

R. U. Agu, S. Valiveti, D. C. Earles, M. Klausner, P. J. Hayden, D. P. Wermeling and A. L. Stinchcomb, Intranasal delivery of recombinant human parathyroid hormone [hPTH (1-34)], teriparatide in rats, Endocr. Res. 30 (2004) 455-467; DOI: 10.1081/ERC-200035957.

N. V. Chemuturi, P. Hayden, M. Klausner and M. D. Donovan, Comparison of human tracheal/bronchial epithelial cell culture and bovine nasal respiratory explants for nasal drug transport studies, J. Pharm. Sci. 94 (2005) 1976-1985; DOI: 10.1002/jps.20404.

R. U. Agu, H. Vu Dang, M. Jorissen, R. Kinget and N. Verbeke, Metabolism and absorption enhancement of methionine enkephalin in human nasal epithelium, Peptides 25 (2004) 563-569; DOI: 10.1016/j.peptides.2004.02.019.

N. Denora, V. Laquintana, A. Lopedota, M. Serra, L. Dazzi, G. Biggio, D. Pal, A. K. Mitra, A. Latrofa, G. Trapani and G. Liso, Novel L-dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety, Pharm. Res. 24 (2007) 1309-1324; DOI: 10.1007/s11095-007-9255-y.

P. K. Yeung, A. Jamieson, G. J. Smith, D. Fice and P. T. Pollak, Determination of plasma concentrations of losartan in patients by HPLC using solid phase extraction and UV detection, Int. J. Pharm. 204 (2000) 17-22; DOI: 10.1016/S0378-5173(00)00453-1.

A. Soldner, L. Z. Benet, E. Mutschler and U. Christians, Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and Caco-2 cell monolayers, Br. J. Pharmacol. 129 (2000) 1235-1243; DOI: 10.1038/sj.bjp.0703150.

M. D. Ribadeneira, B. J. Aungst, C. J. Eyermann and S. M. Huang, Effects of structural modifications on the intestinal permeability of angiotensin II receptor antagonists and the correlation of in vitro, in situ, and in vivo absorption, Pharm. Res. 13 (1996) 227-233; DOI: 10.1023/A:1016086930019.

O. von Richter, O. Burk, M. F. Fromm, K. P. Thon, M. Eichelbaum and K. T. Kivistö, Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens, Clin. Pharmacol. Ther. 75 (2004) 172-83; DOI: 10.1016/j.clpt.2003.10.008.

B. I. Florea, I. C. van der Sandt, S. M. Schrier, K. Kooiman, K. Deryckere, A. G. de Boer, H. E. Junginger and G. Borchard, Evidence of P-glycoprotein mediated apical to basolateral transport of flunisolide in human broncho-tracheal epithelial cells (Calu-3), Br. J. Pharmacol. 134 (2001) 1555-1563; DOI: 10.1038/sj.bjp.0704390.

T. Korjamo, P. Honkakoski, M. R. Toppinen, S. Niva, M. Reinisalo, J. J. Palmgrén and J. Mönkkönen, Absorption properties and P-glycoprotein activity of modified Caco-2 cell lines, Eur. J. Pharm. Sci. 26 (2005) 266-279; DOI: 10.1016/j.ejps.2005.06.004.

Z. Shao, R. Krishnamoorthy and A. K. Mitra, Cyclodextrins as nasal absorption promoters of insulin: mechanistic evaluations, Pharm. Res. 9 (1992) 1157-1163; DOI: 10.1023/A:1015847604654.

M. A. Bagger, H. W. Nielsen and E. Bechgaard, Nasal bioavailability of peptide T in rabbits: absorption enhancement by sodium glycocholate and glycofurol, Eur. J. Pharm Sci. 14 (2001) 69-74; DOI: 10.1016/S0928-0987(01)00146-4.

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