**18. Safety of bile acids and probiotics**

Many studies have been conducted to test the toxicity and safety of primary and secondary bile salts and their derivatives. Some bile salts have excellent safety profiles while others are not safe. Bile salts can be used as therapeutic agents, as absorption enhancers and as formulation excipients. Deoxycholic acid is used in manufacturing steroids and in vaccine production (e.g. influenza vaccine). However, its use is severely limited by its narrow safety profile. In relatively high doses, deoxycholic acid can cause

Potentials and Limitations of Bile Acids and Probiotics in Diabetes Mellitus 389

bioavailability. However, it does not allow transport of high molecular weight proteins and peptides. Bile acids have demonstrated the ability to enhance the nasal absorption of insulin and other drugs. One of the main disadvantages of the applications of bile acids as permeation enhancers is that the greater the bile acid is at promoting permeation of through mucosa, the more toxic it becomes. Accordingly, it is important to determine the mechanism of action by which bile acids enhance absorption in order to design absorption promoting agents that are not toxic or irritant. In addition, knowledge of the mechanism of action may allow prediction of the exact amount of a therapeutic substance that will reach the systemic circulation. The metabolism and deconjugation of bile acids are brought about by the gut microflora. Interestingly, gut microflora plays a major rule in energy balance and gut inflammation. Probiotics have shown hypoglycemic effect, when administered alone, thus,

Type 1 diabetes and its complications cannot be cured by the best most intensive insulin therapy (Shamoon et al. 1993). This clearly emphasizes the fact that the disease is more complex, interdependent, and challenging to treat than being a simple hyperglycemia. That is why, in our opinion, multidrug approach which integrates a comprehensive, targeted,

This work has been supported by Ministry of Science and Technology of Serbia Research

Agu, R.U., Jorissen, M., Willems, T., Augustijns, P., Kinget, R. & Verbeke, N. (2001a) In-vitro

Akerblom, H.K., Vaarala, O., Hyoty, H., Ilonen, J. & Knip, M. (2002) Environmental factors

Al-Salami, H., Butt, G., Fawcett, J.P., Tucker, I.G., Golocorbin-Kon, S. & Mikov, M. (2008a)

of gliclazide in diabetic rats. *Eur.J.Drug Metab Pharmacokinet.*, 33, 101-106. Al-Salami, H., Butt, G., Fawcett, J.P., Tucker, I.G., Golocorbin-Kon, S. & Mikov, M. (2008b)

Al-Salami, H., Butt, G., Tucker, I., Fawcett, P.J., Golocorbin-Kon, S., Mikov, I. & Mikov, M.

Al-Salami, H., Butt, G., Tucker, I. & Mikov, M. (2008c) Influence of the semisynthetic bile

*European Journal of Drug Metabolism and Pharmacokinetics*, 34, 43-50.

delivery studies. *Journal of Pharmacy and Pharmacology*, 53, 1447-1456. Agu, R.U., Ugwoke, M.I., Armand, M., Kinget, R. & Verbeke, N. (2001b) The lung as a route

in the etiology of type 1 diabetes. 115, 18-29.

*Pharmacokinetics*, 33, 101-106.

*Pharmacol.Rep.*, 60, 532-541.

nasal drug delivery studies: comparison of derivatised, fibrillar and polymerised collagen matrix-based human nasal primary culture systems for nasal drug

for systemic delivery of therapeutic proteins and peptides. *Respiratory Research*, 2,

Probiotic treatment reduces blood glucose levels and increases systemic absorption

Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats. *European Journal of Drug Metabolism and* 

(2009a) Gliclazide reduces MKC intestinal transport in healthy but not diabetic rats.

acid (MKC) on the ileal permeation of gliclazide in healthy and diabetic rats.

and tailored treatment should guarantee the best outcome for diabetic patients.

their use in T1D should be studied further.

**20. Acknowledgement** 

198-209.

grant No 41012.

**21. References** 

hepatotoxicity and can damage the gastric mucosa. Cholylsarcosine (CS) is a stable bile salt derivative of deoxycholic acid. It resists bacterial activation to the more toxic bile acid, deoxycholic acid, and thus has a good safety profile. It is commonly used as an absorption enhancer in the treatment of primary biliary cirrhosis (Ricci et al. 1998). Deoxycholic acid salt is also used in the formulation of Amphotericin B, which is commonly used for treating fungal infections of the eyes (Samiy et al. 1996). However, due to its limited safety profile, Amphotericin B in doses as low as 1 µg has been shown to cause retinal damage despite the fact that the recommended dose is 5-10 µg (Souri & Green 1974). The administration of Amphotericin B deoxycholate may also result in cataract formation, opacity, retinal necrosis and retinal ganglion cell loss (Cannon et al. 2003).

When it comes to predicting the toxicity of bile salts, it seems that toxicity increases with their permeation ability. The more capable bile salts are to solubilizing membrane proteins, the more toxic they are (Shao et al. 1992a). In one study (Hersey & Jackson 1987b), bile acids damaged nasal epithelium causing nasal irritation, congestion and bleeding. The authors concluded that nasal applications of bile salts should be limited with infrequent dosing regimen.

Formulation of bile salts in inhalations can cause pulmonary oedema, when inhaled in large quantities. This is due to the solubilization and dissolution of the pulmonary membranes and pulmonary hemorrhage (Kaneko et al. 1990). However, such side effects are only caused by largely inhaled doses.

Probiotic administration has shown good safety profile in individuals with overall good health status, and may be suffering from mild infections or GI disorders (Luoto et al. 2010). Probiotic safety stems from the fact that many strains are of human origin and present in large numbers in human GIT (Rozanova & Voevodin 2008). Accordingly, the reported incidences of probiotics inducing bacterial infection and bacteremia are very low (Snydman 2008). The only major concern with probiotic administration is the potential of bacterial translocation resulting in the induction of antibiotic-resistance strains that may lead to pathogenesis and haemodyscrasia (Liong 2008; Snydman 2008). Having said that risks of infections caused by probiotic treatment is expected to be significant in immunocompromised patients (Marteau & Shanahan 2003; Rayes et al. 2005).

If the use of probiotics and bile acids is to become part of T1D therapy, their safety concerns may be overcome by thoroughly studying appropriate dosing and frequency, their short and long term effect on mucosal membranes and the variation of their effect in different populations.
