Intestine chemical modification

K. Yamada, M. Murakami, A. Yamamoto, K. Takada, S. Muranishi, Improvement of Intestinal Absorption of Thyrotropin-Releasing Hormone by Chemical Modification with Laurie Acid , J. Pharm. Pharmacol. 1992, 44, 717-721. 

Rowell etal. (1987b) produced PF-bonded flakeboard from acetylated southern pine (21.6 % WPG) or aspen (17.6 % WPG) flakes. This was not completely resistant to attack by termites Reticulitermes flavipes) in a 4-week test. It was thought that acetylation was less effective in preventing termite attack than other chemical modifications because cellulose decomposition in the intestines of termites leads to acetic acid formation in any case. 

Fujita, T., Fujita, T., Morikawa, K., et al. Improvement of intestinal absorption of human calcitonin by chemical modification with fatty acids Synergistic effects of acylation and absorption enhancers. Int. J. Pharm. 134 47—57, 1996. 

Hashizume, M., Douen, T., Murakami, M., et al. Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats. J. Pharm. Pharmacol. 44 555-559, 1992. 

Detoxification of dietary alleochemicals, which can be achieved by symbiotic bacteria or protozoa living in the rumen or intestines, or by liver enzymes which are specialized for the chemical modification of xenobiot-ics. This evolutionary trait is very helpful for Homo sapiens, since it endowed us with a means to cope with our man-made chemicals which pollute the environment. Carnivorous animals, such as cats, are known to be much more sensitive toward plant poisons (505). It was suggested that these animals, which do not face the problem of toxic food normally, are thus not adapted to the handling of allelochemicals. 

The above-mentioned enzymatic barriers must be overcome to improve oral absorption of peptide and protein drugs from the GI tract. This may be possible to achieve to some extent by the coadministion of proteolytic enzyme inhibitor or by chemical modification of peptides or proteins and by other formulation approaches (see section Intestinal Absorption of Amino Acids, Peptides, and Proteins, later). 

To minimize degradation and improve absorption of peptide and protein drugs administered orally, several factors are significant. First, peptide and protein drugs have to be protected from the acidic environment in the stomach and from enzyme degradation in the lumen and on the brush border of the small intestine. This may be accomplished by coadministration of peptidase inhibitors or by chemical modifications, such as analogs or prodrug approaches, or... 

Second, because of their molecular size and hydrophilic nature, peptide and protein drugs are poorly absorbed through the intestinal membrane, and absorption has to be improved. This may be accomplished by coadministration of penetration enhancers or by chemical modifications such as increasing lipo-philicity. 

In this chapter, we summarize the general approaches that have been used to successfully achieve the formulation goals for oral delivery minimize enzymatic degradation enhance intestinal absorption maximize blood level reproducibility deliver drug through the gut wall and produce a palatable and acceptable dosage form. Then insulin will be used as an example to show how oral bioavailability has been achieved through chemical modification. 

Yamamoto A. [Improvement of intestinal absorption of peptide and protein drugs by chemical modification with fatty acids]. Nippon Rinsho 1998 Mar 56(3) 601-607. Japanese. 

TG was reduced by chemical modification with fatty acids, which resulted in an increase in the transport of TG across Caco-2 monolayers. In addition, the permeation clearance (GLp) value of carboxyfluorescein (GF), a paraceUular transport and unde-gradable marker, increased in the presence of acyl-TGs. Thus, we demonstrated that acyl-TGs have the ability to enhance absorption of molecules, including themselves, across Gaco-2 monolayers. These findings indicated that chemical modification of TG with various fatty acids could improve its transport across both intestinal membrane and Caco-2 cell monolayers. 

Some bacterial toxins contain a subunit that penetrates the plasma membrane of cells and catalyzes a chemical modification of Gscj-GTP that prevents hydrolysis of bound GTP to GDP. As a result, remains in the active state, continuously activating adenylyl cyclase in the absence of hormonal stimulation. Cholera toxin produced by the bacterium Vibrio cholera and enterotoxlns produced by certain strains of E. coll act in this way on intestinal epithelial cells. The resulting excessive rise in Intracellular cAMP leads to the loss of electrolytes and water into the intestinal lumen, producing the watery diarrhea characteristic of infection by these bacteria. 

When the pharmaceutical formulation of an active compound is ineffective, slight chemical modifications or formation of bioreversible derivatives (esters, amides, peptides) can improve its physico-chemical properties (lipophilicity, pK, polarity) and optimize the dissolution rates in the biological fluids and the passage through the very first biological membranes (cutaneous, intestinal, etc.). The global result is better penetration into the organism. Compared with the pharmaceutical formulation mentioned above, this process can be considered as a chemical formulation and will be considered in Chapter 39. 

An example is the increase in lipid solubility achieved by chemical modification by tetracycline to give the derivative doxycycline. Doxycycline (Vibramycin) is more efficiently absorbed from the intestine than is tetracycline, partly because of better lipid solubility and partly because of a decreased tendency to form poorly soluble complexes with calcium. 

---