**11. Bile acids as absorption enhancers in Type 1 diabetes therapy**

Bile acids and their derivatives can act as absorption enhancers where they are capable of promoting mucosal and systemic drug absorption. Bile acids and their derivatives can increase drug bioavailability, allowing therapeutic doses to be administered by several routes. Bile acids as therapeutic agents have the potential to produce beneficial effects in improving primary biliary cirrhosis and primary sclerosing cholangitis. Bile acids can also control endocrine signalling and enzymatic activities in various disorders. This includes inflammatory diseases (such as diabetes) and cholestatic liver disease in cystic fibrosis.

Permeation of a drug through a biological membranes by passive diffusion is influenced by the drug's solubility and molecular weight, the thickness of both, the mucous and the cytoplasmic membrane, while drug diffusibility is influenced by permeability, surface area and the concentration gradient (Higgins & Gottesman 1992; Maki et al. 2003; Mao & Unadkat 2005; Neubert et al. 1987).

Bile salts (conjugated bile acids) are known to increase the permeation of many drugs. They increase the permeability of the mucosal membrane by breaking down mucous and disrupting cells, thus widening the tight junctions between these cells. This enhances penetration of drugs via the paracellular route. Bile salts can also improve transcellular absorption by increasing drug solubility and dissolution rate. Bile salts can form micelles which increase the permeability of the mucosal membrane by overcoming resistance at the aqueous diffusion layer. They also enhance drug delivery by interacting with membrane lipids and proteins that affect membrane fluidity and the rate of drug trafficking.

Fig. 3. Protein transporters in the mucosal and serosal sides of the gut enterocytes.

Potentials and Limitations of Bile Acids and Probiotics in Diabetes Mellitus 383

4%. This still remains a limiting factor in insulin clinical applications (25). An estimated 80% of administered drug is eliminated through the nasal cavity after occular application (26). Another study (Yamamoto et al. 1989) determined the extent to which absorption promoters could enhance the absorption of insulin via the ocular route. When administered alone, occular insulin serum levels reached Cmax within 15 minutes of occular administration while when formulated with sodium glycocholate, sodium taurocholate and sodium deoxycholate (as absorption enhancers), insulin Cmax was reached within 5 minutes. When insulin was co-administered with sodium glycocholate, the amount of insulin permeating the eyes and reaching the systemic circulation increased from 1% to 5.5%. Sodium deoxycholate was found to be more effective and sodium taurocholate least effective at enhancing the occular absorption of insulin. This implies a good potential of bile acid

applications in insulin occular delivery in T1D, when other routes as less desirable.

The Nasal route is a convenient and popular method of drug administration as it is feasible and it has fast absorption rate. It also provides reasonable bioavailability as it bypasses first pass hepatic metabolism. However, pharmacologically active peptides such as hormones and proteins with molecular weights > 10 kDa do not have the ability to permeate the nasal mucosal layer without being significantly trapped, washed out (through the nasopharyngeal cavity), or degraded before reaching the systemic circulation. In order to optimise nasal drug delivery to drugs such as insulin, suitable permeation enhancers such as bile salts may be appropriate. For insulin to be delivered nasally, it has to permeate the nasal mucosa and

Fig. 4. The general structure of the eye.

**14. Nasal absorption** 

Recent studies suggest a bigger role for Mdr and Mrp transporters in the enterohepatic recirculation of bile acids (Asamoto et al. 2001). Mrp2 and Mrp3 recognize monovalent (those with a single charge) and divalent (those with a double charge) bile acids as their substrates (St-Pierre et al. 2000; St-Pierre et al. 2001; Zollner et al. 2003) while Mdr1 and Mdr3 recognise bile acid taurocholate, glutathione, bile salt glucuronide and sulfate conjugates (Ballatori et al. 2005a; Ballatori et al. 2005b). Mrp2 is located in the apical membrane of the bile canaliculus where it removes newly formed divalent bile acids into the bile duct. Mrp3 is located in the basolateral membrane of the ileal enterocytes where it removes monovalent bile acids from the gut lumen into the portal vein (Houten et al. 2006a). Figure 3 shows the locations of a mucosal and a serosal protein transporters (mucosal transporter is in green & serosal transporter is in red) expressed in enterocytes.
