Gastrointestinal tract phases

Cytochrome P4502E1, also microsomally located, catalyzes the hydroxylation of phenol to form hydroquinone (and to a much lesser extent catechol), which is then acted upon by the phase II enzymes (Benet et al. 1995 Campbell et al. 1987 Gut et al. 1996 McFadden et al. 1996). All three enzyme systems are found in multiple tissues and there is competition among them not only for phenol but for subsequent oxidative products, like hydroquinone. As a consequence, the relative amount of the products formed can vary based on species, dose and route of administration. In vivo, the gastrointestinal tract, liver, lung, and kidney appear to be the major sites of phenol sulfate and glucuronide conjugation of simple phenols (Cassidy and Houston 1984 Powell et al. 1974 Quebbemann and Anders 1973 ... 

In animals, absorption of 3,3 -dichlorobenzidine from the gastrointestinal tract is rapid. Following a dose of 40 mg/kg, the plasma level of imchanged 3,3 -dichlorobenzidine attained a peak concentration of 1.25 g/mL at 4 hours in Sprague Dawley rats. Further, about 90% of the administered radioactivity was excreted in feces (via bile) and urine within 72 hours largely as metabolites, indicating a high bioavailability, typical of primary aiylamines. The elimination is biphasic, with half-lives of 6 hours and 14 hours in plasma for the rapid and slow phases, respectively (Hsu and Sikka 1982). 

Klinkenbijl JH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999 230(6) 776-782 discussion 782-784. 

Since the first series of compounds were poorly soluble in water, the next crucial phase of the project set out to increase the water solubility of the drug candidates in order to increase absorption from the gastrointestinal tract. Further refinements led to a candidate that was not only well absorbed when administered orally to animals, but also had outstanding antimalarial profiles both in vitro and in vivo. In comparison to available semi-synthetic artemisinins, the drug candidate OZ 277 (Scheme 27) exhibits structural simplicity, an economically feasible and scalable synthesis, superior antimalarial activity and an improved pharmaceutical profile. The toxicological profiles are also acceptable and this drug candidate entered first into man studies during 2004. 

Sulfonic Acids. Drugs that contain sulfonic acids are quite acidic. They have high water solubility and are rapidly excreted, leading to a rather short half-life. They can also be irritating to the gastrointestinal tract during the pharmaceutical phase. 

It acts by inhibiting dihydrofolate reductase. It inhibits conversion of dihydrofolic acid to tetrahydrofolic which is essential for purine synthesis and amino acid interconversions. It primarily affects DNA synthesis but also RNA and protein synthesis. It has cell cycle specific action and kills cells in S phase. It is readily absorbed from gastrointestinal tract but larger doses are absorbed incompletely, little drug is metabolised and it is excreted largely unchanged in urine. 

Knowing the differential pharmacokinetics for a class of drugs allows the clinician to choose specific members to either achieve a faster onset or a delayed offset of action (13, 14, 17, 18). For example, lorazepam is rapidly absorbed from the gastrointestinal tract into the systemic circulation and from there distributed into the brain. In contrast, oxazepam, the most polar BZD, is slowly absorbed from the gastrointestinal tract. Even after oxazepam is in the systemic circulation, it slowly enters tissue compartments, including the brain, during the distribution phase. Unlike lorazepam, oxazepam is not available in either the intramuscular or intravenous formulations. Thus, lorazepam would be preferable to achieve acute control of alcohol withdrawal (e.g., delirium tremens), whereas oxazepam would better stabilize a dependency-prone patient on sedative-hypnotics, because it does not cause the euphoria seen with the more rapidly absorbed members of this class. 

The amide local anesthetics are widely distributed after intravenous bolus administration. There is also evidence that sequestration can occur in lipophilic storage sites (eg, fat). After an initial rapid distribution phase, which consists of uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well-perfused tissues, such as muscle and the gastrointestinal tract. As a result of the extremely short plasma half-lives of the ester type agents, their tissue distribution has not been extensively studied. 

Aminoglycosides are absorbed very poorly from the intact gastrointestinal tract almost the entire oral dose is excreted in feces after oral administration. However, the drugs may be absorbed if ulcerations are present. After intramuscular injection, aminoglycosides are well absorbed, giving peak concentrations in blood within 30-90 minutes. Aminoglycosides are usually administered intravenously as a 30- to 60-minute infusion after a brief distribution phase, this results in serum concentrations that are identical with those following intramuscular injection. 

Biological factors. The species of animal is a very important factor especially affecting metabolism but also influencing the other phases of disposition. The pH of the gastrointestinal tract, the nature of the skin, and breathing rate all may affect absorption. Plasma proteins and fat can affect distribution. Biliary excretion is affected by species in relation to the molecular weight threshold. 

Kossena, G. A., W. N. Charman, B. J. Boyd, D. E. Dunstan, and C. J. H. Porter. 2004. Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems A phase diagram approach).. Pharm. Sci93 332-348. 

The symptoms of mushroom poisoning vary. Typical early symptoms involve the gastrointestinal tract and include stomach pains and cramps, nausea, vomiting, and diarrhea. Victims in the second phase of severe poisoning may suffer paralysis, delirium, and coma, along with often severe liver damage. 

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