Macromolecules oral administration

Pilon D, Roberts AE, Rickert DE. 1988a. Effect of glutatione depletion on the irreversible association of acrylonitrile with tissue macromolecules after oral administration to rats. Toxicol Appl Pharmacol 95 311-320. 

Immediately following inhalation of labelled methyl chloride by rats, up to 20% of the label was incorporated into tissue macromolecules. After 6 h, the total level of non-volatile label was highest in liver and kidney and lower in testes. Within 24 h, about 64% of the label was exhaled, 32% found in urine and about 4% in faeces. About 50% of the radio-label was expired as [ C]CO2. Following oral administration, radioactivity in hepatic proteins was associated with methionine and serine. 

Of particular interest for the oral administration of macromolecules, be they peptides or nucleic acids, is the potential of oral vaccines that could revolutionise the health care of millions of people, particularly in developing countries. 

One of the biggest impediments of oral administration of macromolecules is their lack of stability in the gastrointestinal tract. Indeed, the majority of macromolecules such as peptides, proteins, oligonucleotides, and various types of RNA undergo enzymatic degradation before reaching their site of action or absorption. One of the strategies used to circumvent this problem is to incorporate such compounds into nano- or microcarriers. These carriers... 

Permeation of macromolecules through the GI epithelial cells after oral administration has been reported by several research groups. We have also confirmed the permeation of the hydrophilic macromolecules by using Caco-2 cells (Nagata et al. 2006). However, there are no data clearly showing the actual absorption of macromolecular drugs into the GI tract after oral administration. 

The particular complexities of antibody pharmacokinetics and their relationship to pharmacodynamics have been thoroughly reviewed by Lobo and coworkers [16]. Many of the characteristics discussed above for macromolecules in general also apply in the case of antibodies. Thus, absorption following subcutaneous or intramuscular administration may be slow, with involvement of lymphatic transport, and attainment of peak blood concentrations may take days. Although absorption of antibodies from the gastrointestinal tract following oral administration to adult humans is very limited, absorption of IgG from the gastrointestinal tract of neonates of several species has been demonstrated [34]. This absorption occurs via interaction with the neonatal receptor for... 

With few exceptions, such as peptides and hormones, drugs and their precursors are typically low-molecular-weight compounds and, therefore, haptens. To build a complete antigen, they must bind to macromolecules e.g. human tissue or serum proteins. Some drugs are primarily reactive while, in others, reactive metabolites are only generated in vivo. Oral administration is usually better tolerated and may even induce tolerance. However, intermittent exposure by epi- or intradermal application or by inhalation, as it typically occurs in occupational settings, carries the highest risk of sensitization (Bircher 1996). 

Transport in the reverse direction, i.e. intestinal absorption of polymers after oral administration, has been demonstrated to depend on the molecular weight Large molecules are mostly unable to undergo intestinal absorption In a study with I-labelled PVP, its absorption was found to be independent of the amount of I-PVP infused, suggesting the existence of a readily saturated absorption mechanism The presence of a mucus layer on the luminal side of the epithelial cells may contribute to a selective exclusion of macromolecules (see below)... 

A study by Young et al. (1977) showed that retention and excretion of acrylonitrile are not directly proportional to dose. The data suggest a saturation process, perhaps due to covalent binding to tissue macromolecules. Seventy-two hours after administration of single oral doses of either 0.1 or 10 mg/kg, the proportion of the dose retained in the carcass was 37% at the low dose (0.1 mg/kg) and 27% at the high dose (10 mg/kg). 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

Because most proteins are susceptible to protease degradation and denaturation in biologic fluids, most biopharmaceuticals must be administered by intravenous, intramuscular, or subcutaneous injection (see Table 5.5). High concentrations of proteases are found in the gastrointestinal tract, nasal mucosa, bronchioles, and alveoli, which severely limit the bioavailability of protein pharmaceuticals after oral, intranasal, and inhalation administration. Diffusional barriers to the passage of relatively large macromolecules preclude transdermal and mucosal administration of protein pharmaceuticals. Research is under way to develop methods that will protect protein drugs from proteolysis and improve transmembrane diffusion. 

Ahmed et al. (1982) examined the distribution of [l- Cjacrylonitrile (46.5 mg/kg bw orally) in rats. Some 55% of the dose was recovered in the excreta in 24 h (urine, 40% faeces, 2% exhaled as CO . 9% as H (. 0.5% and acrylonitrile, 4.8%). In addition to appreciable retention in the erythrocytes (a feature of the behaviour of meta-bolically formed thiocyanate noted by Bollard et al., 1997), there occurred covalent binding to tissue macromolecules in liver, kidney, spleen, brain, limg and heart. Ahmed et al. (1983) also compared the tissue distribution of [l- C]- and 2,3- - C]aciylonitrile in rats at the same dose level (46.5 mg/kg bw). There was much more covalent binding of radioactive species in all organs examined after administration of [2,3- - C]acr lo-nitrile, suggesting that metabolites other than thiocyanate play a major role in its retention in the body. 

During the past few decades, a number of important studies were published on the effect of cholic acid derivatives on the absorption of macromolecules [81]. Guarini and Ferrari [84—86] compared simultaneous oral dosing of NaDOC and heparin to pretreatment with NaDOC by oral gavage in dogs followed by oral heparin administration at a 0.5-24-h interval. In all pretreatment regimens, NaDOC enhanced heparin absorption, with the maximum effect observed when heparin was administered 1 h after NaDOC. 

A variety of diseases affect the lymphatic system early in their time course. For example, many cancers spread by lymphatic dissemination, and HIV, fungal, and bacterial infections are located primarily in the lymph nodes. The high prevalence of lymph node involvement in disease is due to the role of lymphatic tissue in the provision of the body s immune response. Intralymphatic and interstitial administration are two efficient access routes. However, the oral route may also prove to be important for the lymphatic uptake of lipophilic drags and macromolecules. 

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