Permeacija losartana kroz humani respiratorni epitel: In vitro ispitivanja na Calu-3 stanicama

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--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--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--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.U radu je ispitivana mogućnost nazalne primjene losartana, lijeka sa slabom bioraspoloživošću nakon peroralne uporabe, koristeći Calu-3 stanice. Ispitivana je permeacija lijeka kroz epitel u prisutnosti dimetil-β-ciklodekstrina (DM--CD) i glikokolata te bez njihove prisutnosti. Predložen je mogući mehanizam transporta kroz epitel i određena je tolerancija epitelne mukoze. Reverzibilnost promjena u epitelu praćena je mjerenjem povrata transepitelnog električnog otpora (TEER) kroz razdoblje od 24 h nakon izlaganju pripravku lijeka. Koeficijent permeabilnosti losartana bio je 1.3 ± 0.46 × 106 cm s1. Taj se dotok značajno ne razlikuje od pripravaka koji sadrže DM--CD (0,5 i 1,0 %), odnosno glikokolat (0,5 %) (faktor povećanja 1,0). Međutim, iz pripravka s 1,0 % glikokolata povećala se permeacija losartana 7 puta. Protok losartana kroz stanice ovisio je o koncentraciji. Permeacija iz seruma u mukozu bila je značajno veća nego u obrnutom smjeru. Ovisnost o koncentraciji te polarnost u transportu ukazuju na to da protok losartana kroz Calu-3 stanice nije ograničen samo na pasivnu difuziju. Stanice izložene dimetil-β-ciklodekstrinu (0,5 i 1,0 %) i glikokolatu (0,5 %) nisu uzrokovale značajne promjene TEER-a i aktivnosti mitohondrijske dehidrogenaze (MDH). Rezultati pokazuju da je losartan pogodan za nazalnu isporuku