Poor absorption

Toxicology. Inorganic tin and its compounds are generally of a low order of toxicity, largely because of the poor absorption and rapid excretion from the tissues of the metal (42—49). The acidity and alkalinity of their solutions make assessment of their parenteral toxicity difficult. The oral LD q values for selected inorganic tin compounds are Hsted in Table 2. It is estimated that the average U.S. daily intake of tin, which is mostly from processed foods, is 4 mg (see Food processing). 

Since about 85% of the administered dose is passed unchanged in the feces of the patient, selective toxicity of the dmg can be attributed primarily to poor absorption. Side effects include abdominal pain, nausea, vomiting, diarrhea, loss of appetite, headaches, and vertigo or drowsiness. Skin rashes can also develop. Pyrantel pamoate is produced by Pfi2er, Inc., New York, New York. 

In general the lanthanides, including cerium, have a low toxicity rating (17), especially when they are present in material having low aqueous solubiUty. When orally adrninistered poor absorption from the gastrointestinal tract tends to result in the lanthanides generally having Httle effect. The anion is often an important deterrninant in toxicity. 

In recent years, many parent dmgs have been converted to esters to generate so-called prodmgs ia order to overcome some undesirable property such as bitter taste, poor absorption, poor solubiUty, and irritation at site of iajection. For example, antibiotics such as chloramphenicol [56-75-7] and clindamycin [18323-44-9] have been derivatized as their palmitate esters ia order to minimise their bitter taste. 

PuAEMACoLOGiCAL AcTiox. Curare is stated to be almost inert when taken by mouth, owing to poor absorption by intestinal mucous membrane and the rapidity of elimination. Injected hypodermically it is a rapid and potent poison, paralysing the motor nerve-endings in striped muscle, so that voluntary movements cease and death occurs from respiratory failure. 

Since many of the uses of antihistamines involve conditions such as rashes, which should be treatable by local application, there is some rationale for developing drugs for topical use. The known side effects of antihistamines could in principle be avoided if the drug were functionalized so as to avoid systemic absorption. The known poor absorption of quaternary salts make such derivatives attractive for nonabsorbable antihistamines for topical use. Thus, reaction of the well-known anti his-taminic drug promethazine (104) with methyl chloride leads... 

In the vitamin D deficiency disease rickets, the bones of children are undermineralized as a result of poor absorption of calcium. Similar problems occur in adolescents who are deficient during their growth spurt. Osteomalacia in adults results from demineralization of bone in women who have little exposure to sunlight, often after several pregnancies. Although vitamin D is essential for prevention and treatment of osteomalacia in the elderly, there is little evidence that it is beneficial in treating osteoporosis. 

The metabolic and pharmacokinetic profile of sucralose (this is a novel intense sweetener with a potency about 600 times that of sucrose) in human volunteers was studied by Roberts and coworkers [82]. Part of this study was realized using PLC in the following chromatographic system in which the stationary phase was silica gel and the mobile phase was ethyl acetate-methanol-water-concentrated ammonia (60 20 10 2, v/v). Separated substances were scraped off separately, suspended in methanol, and analyzed by filtration, scintillation counting, or enzymatic assay. It was shown that the characteristics of sucralose include poor absorption, rapid elimination, limited conjugative metabolism of the fraction absorbed, and lack of bio-accumulative potential. 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

Lipinski et al. at Pfizer [11] analyzed the distribution of physicochemical properties of 2245 drugs from the WDI that have entered clinical trials after excluding natural products and actively transported molecules. They proposed the Rule-of-5 to indicate that poor absorption or permeation is more likely when ... 

Oral iron supplementation is generally not effective in maintaining adequate iron stores in patients receiving ESAs because of poor absorption and an increased need for iron with ESA therapy, making the IV route necessary for iron supplementation. The IV iron products currently available are iron dextran (distributed as INFeD by Watson Pharmaceuticals, Inc., Morristown, NJ, and Dexferrum by American Reagent, Inc.,... 

Since there is no true excretion of iron from the body, iron-deficiency anemia occurs mostly because of inadequate absorption of iron or excess blood loss. Inadequate absorption may occur in patients who have congenital or acquired intestinal diseases, such as inflammatory bowel disease, celiac disease, or bowel resection. Achlorhydria and diets poor in iron also may contribute to poor absorption of iron. In contrast, iron deficiency also may occur in patients who exhibit a higher rate of iron loss from the body. This is manifested in... 

Based upon a review of the physical chemical properties of marketed drugs, Lipinski and coworkers have proposed an empirical rule of 5 (20). This rule may help pharmaceutical scientists in reaching an early decision about the potential candidacy for further development of a new chemical entity. The rule states that a chemical candidate is likely to display poor absorption or poor membrane permeability if... 

Since many essential nutrients (e.g., monosaccharides, amino acids, and vitamins) are water-soluble, they have low oil/water partition coefficients, which would suggest poor absorption from the GIT. However, to ensure adequate uptake of these materials from food, the intestine has developed specialized absorption mechanisms that depend on membrane participation and require the compound to have a specific chemical structure. Since these processes are discussed in Chapter 4, we will not dwell on them here. This carrier transport mechanism is illustrated in Fig. 9C. Absorption by a specialized carrier mechanism (from the rat intestine) has been shown to exist for several agents used in cancer chemotherapy (5-fluorouracil and 5-bromouracil) [37,38], which may be considered false nutrients in that their chemical structures are very similar to essential nutrients for which the intestine has a specialized transport mechanism. It would be instructive to examine some studies concerned with riboflavin and ascorbic acid absorption in humans, as these illustrate how one may treat urine data to explore the mechanism of absorption. If a compound is... 

An alternative to GI retention for drugs with poor absorption characteristics is to use chemical penetra-... 

Poor absorption is likely whenever two or more of the following rules are invoked... 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

Reduced absorption due to complex formation or other interactions between drugs and intestinal components leading to poor absorption has been described in a few cases. One example is the precipitation of cationic drugs as very poorly-soluble salts with bile acids, which has been reported for several compounds [62], Another well-known example is the complex formation between tetracycline together with calcium due to chelation after administration of the drug together... 

Inorganic tin compounds and some heterocyclic organic tin compounds are of low toxicologic risk to mammals (Table 8.11), due largely to their low solubility, poor absorption, low tissue accu-... 

One of the simplest and most common ways to evaluate a molecule for ADME properties is a qualitative examination of its basic descriptor values such as molecular weight (MW), ClogP for lipophilicity, polar surface area (PSA), counts of hydrogen bond donors and acceptors (HBD, HBA), and count of rotatable bonds (RB). This type of approach popularized by Lipinski s famous Rule of 5 was published a decade ago [6]. Lipinski et al. established cutoffs for MW (500), ClogP (5), HBA (10), and HBD (5). These cutoffs were based on the 90th percentile of distributions of molecules in the World Drug Index having USAN or INN names. The Rule of 5 considers a violation of any two of these cutoffs to be an alert for poor absorption or permeability. 

Some optically active compounds have been studied [54], The benzazepinone diacid (CGS 12831, 27) was found to have the best in vitro inhibitor potency in a series of lactam compounds, but it showed only marginal biological activity following oral administration, presumably because of poor absorption. The corresponding monoethyl ester (CGS 14824A, 28) was much more potent in vivo [54, 56]. This compound (28) was found to produce dose-dependent antihypertensive effects in conscious normotensive and spontaneous hypertensive rats, generally similar to those produced by enalapril. Evaluation of (28) in healthy volunteers [57, 58] shows that it is an effective,... 

Dosing techniques, such as intramuscular, intradermal, subcutaneous, and intra-peritoneal administration, can be used for the ferret. Care needs to be taken, however, when administering lipophilic compounds by the subcutaneous or intradermal routs, to avoid inadvertently injecting compounds into the ferret s thick layer of subcutaneous fat, which can result in poor absorption (Moody et al., 1985). 

It is most convenient to determine the spectrum in solutions. Excellent solvents are those that have poor absorptions of their own. These solvents absorbs in one region or the other. Some important solvents are (/) Chloroform (ii) carbon tetrachloride or (iii) carbon disulphide. 

Particle size of the sample has got to be reduced below 200 mesh or 3 pm so as to avoid scattering of radiation thereby causing poor absorption spectrum. 

Vitamin D deficiency may also occur through inadequate dietary intake, gut (poor absorption), renal disease (1-hydroxylase deficiency or failure to reclaim calcium from the glomerular filtrate), or liver disease (25-hydroxylase deficiency). The slightly low haemoglobin concentration and pale stained (hypochromic) red cells suggested a coincident mild iron deficiency. 

It seems likely that most of the losses following topical aldrin application are due to poor absorption rather than to elimination. The intramuscular route is being used as a means to obtain long-term, low level exposures. Since these procedures permit in situ administration of test compounds, an operation difficult or impossible with the more common immersion strategy for dosing, intramuscular injections will receive increased attention and evaluation. 

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