Bile salts and intranasal drug absorption

Abstract

The nasal route has been proven to be very effective for drug absorption. Bioavailability of intranasally administered drugs depends on the structure of the drug and can be as high as 100%. The absorption of drugs with a lower bioavailability can be improved with the aid of absorption promotors such as some surfactants, e.g. bile salts. The intranasal absorption of gentamicin, as a model drug, was studied in rabbits with six different bile salts as absorption promotors (cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate and glycodeoxycholate). Without a surfactant, gentamicin is not absorbed by the nasal mucosa. The serum concentrations of gentamicin after intranasal administration were compared with those obtained after an intravenous injection. Concentrations were measured with EMIT. The bioavailability of the intranasal gentamicin in rabbits was related to the hydrophobicity and the pK a's of the bile salts. Furthermore the effects on ciliated epithelium of the six bile salts, used in the absorption experiment, were studied in an in vitro model. Ciliary activity was studied with a photo-electric method. Bioavailability increased with the increase of the hydrophobicity of the trihydroxy bile salts (cholate, taurocholate and glycocholate). Sodium cholate and sodium taurodeoxycholate were the most active absorption promotors (F = 41 ± 16%, respectively, 34 ± 13%). The dihydroxy bile salts (deoxycholate, taurodeoxycholate and glycodeoxycholate) showed a decreasing activity in the promotion of gentamicin absorption as the hydrophobicity increases. Depending on the pH/pK a relation, increasing hydrophobicity results in lower solubility and therefore decreasing activity. Ciliotoxicity of the bile salts increased with increasing hydrophobicity. Dihydroxy bile salts are more toxic than trihydroxy bile salts. At the used concentrations ciliary beat arrested within 30 min. Deoxycholate is extremely ciliotoxic, ciliary arrest occurred within 1 min at a concentration of 5 mmol/l.