Intestine stability

Dube A, Nicolazzo JA, Larson 1. Chitosan nanoparticles enhance the plasma exposure of (-)-epigaUocatechin gaUate in mice through an enhancement in intestinal stability. Eur J Pharm Sd. 2011 44(3) 422-6. 

Calcium-binding proteins, 6, 564, 572, 596 intestinal, 6, 576 structure, 6, 573 Calcium carbonate calcium deposition as, 6, 597 Calcium complexes acetylacetone, 2, 372 amides, 2,164 amino acids, 3, 33 arsine oxides, 3, 9 biology, 6, 549 bipyridyl, 3, 13 crown ethers, 3, 39 dimethylphthalate, 3, 16 enzyme stabilization, 6, 549 hydrates, 3, 7 ionophores, 3, 66 malonic acid, 2, 444 peptides, 3, 33 phosphines, 3, 9 phthalocyanines, 2,863 porphyrins, 2, 820 proteins, 2, 770 pyridine oxide, 3,9 Schiff bases, 3, 29 urea, 3, 9... 

HFE has been shown to be located in cells in the crypts of the small intestine, the site of iron absorption. There is evidence that it associates with P2 niicroglobu-lin, an association that may be necessary for its stability, intracellular processing, and cell surface expression. The complex interacts with the transferrin receptor (TfR) how this leads to excessive storage of iron when HFE is altered by mutation is under close smdy. The mouse homolog of HFE has been knocked out, resulting in a potentially useful animal model of hemochromatosis. 

Ferruzzi, M.G., Failla, M.L., and Schwartz, S.J., Sodium copper chlorophyllin in vitro digestive stability and accumulation by Caco-2 human intestinal cells, J. Agric. Food Chem., 50, 2173, 2002. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

A complication here, however, is noted with those drugs that exhibit a limited chemical stability in either acidic or alkaline fluids. Since the rate and extent of degradation is directly dependent on the concentration of drug in solution, an attempt is often made to retard dissolution in the fluid where degradation is seen. There are preparations of various salts or esters of drugs (e.g., erythromycin) that do not dissolve in gastric fluid and thus are not degraded there but which dissolve in intestinal fluid prior to absorption. A wide variety of chemical derivatives are used for such purposes. 

ApoC-II is expressed in liver and intestine, and both the neural retina and RPE (Li et al., 2006). In contrast to ApoC-I, it can function as an activator of lipoprotein lipase. Similar to ApoA-I, ApoA-II, and ApoE, in the absence of lipid to stabilize its structure, ApoC-II forms amyloid assemblies. 

Some extended-release preparations are designed with a coating that responds to the acidity of its environment. The polymeric coating of the medicine is formulated for stability during oral delivery and for eventual solubility at the intended organ. The contrasting acidic content of the stomach and the more basic environment of the intestines enable these formulations to function. For example, hydroxypropyl methylcellulose phthalate (HPMCP) (Fig. 14.1.3) is an enteric... 

This was the original hypothesis put forward by Lee (1970) and expanded by Ogilvie et al. (1973). Secretory products of N. brasiliensis do indeed decrease the amplitude of contractions of segments of uninfected rat intestine maintained in an organ bath, but a role for AChE in this phenomenon was discounted due to the heat stability of the parasite factor, and the inability to duplicate the effect with AChE from the electric eel (Foster et al., 1994). Subsequent investigations demonstrated that the suppression of contraction could be duplicated by a 30-50 kDa fraction of secreted products, which contained a protein of 30 kDa that was immunologically cross-reactive with mammalian vasoactive intestinal peptide (VIP). Moreover, an antibody to porcine VIP significantly reduced the inhibitory effect of parasite-secreted products on contraction in vitro (Foster and Lee, 1996). 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

The stability of niclosamide was studied in simulated gastric and intestinal juices, with and without enzymes, after incubation at 37°C. The remaining intact drug and its degradation products (2-chloro-4-nitroaniline and 5-chlorosalicylic acid) were extracted with chloroform/methanol (5 1) and determined by TLC and HPLC. The drug was stable in these media for at least 6 h [68]. 

A stability-indicating HPLC method has been described for niclosamide in artificial gastric and intestinal juices [68],... 

Purified preparations of calf intestinal AP maintained in solution are usually stored in the presence of a stabilizer, which is typically 3 M NaCl. The enzyme also may be lyophilized, but it may experience activity loss with each freeze-thaw cycle. AP is not stable under acidic conditions. Lowering the pH of an AP solution to 4.5 reversibly inhibits the enzyme. It is recommended that all handling, storage, and use of AP be done under conditions >pH 7.0 to maintain the highest possible catalytic activity. 

Various carboxylic acid salts have also been reported. Gallardo35 produced the maleate salt of neomycin which, it was claimed, improved the aqueous stability of the antibiotic. A practically tasteless compound, the citrate salt,has been described by Szyszka3 . Neomycin mandelate has been claimed to be particularly useful in the treatment of urogenital infections3 while the di-hydroxy-dinaphthylmethane-dicarboxylate4(3 and the pamoate salts43,67,68 have a low intestinal absorption and are thus effective treatments for intestinal infections. 

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

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