Entirely absorbed from the gut and paraquat a highly toxic herbicide figure 316 Sufficient paraquat is absorbed from the gastrointestinal tract after oral ingestion for fatal poisoning to occur but the nature

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of the transport systems for both of these compounds are currently unknown although carrier-mediated transport is perhaps the most likely (see Chapter 7). Carrier-mediated transport systems important for foreign, toxic compounds are known to operate in the gastrointestinal tract. For example cobalt is absorbed via the system that transports iron and lead by the calcium uptake system. Large molecules and particles such as carrageenen and polystyrene particles of 22 *m diameter may also be absorbed from the gut, presumably by phagocytosis. The bacterial product botulinum toxin, a large molecule (molecular weight 200 000-400 000) is sufficiently well absorbed after oral ingestion to be responsible for toxic and often fatal effects.

There are a number of factors which affect the absorption of foreign compounds from the gut or their disposition, one which is of particular importance is the aqueous solubility of the compound in the non-ionized form. With very lipid soluble compounds, water solubility may be so low that the compound is not well absorbed (table 3.2) because it is not dispersed in the aqueous environment of the gastrointestinal tract. Therefore when drugs and other foreign compounds are administered the vehicle used to suspend or dissolve the compound may have a major effect on the eventual toxicity by affecting the rate of absorption. Also the physical form of the substance may be important, for example large particle size may decrease absorption. Similarly, when large masses of tablets are suicidally ingested, even those with reasonable water solubility, such as aspirin (acetylsalicylic acid), the bolus of tablets may remain in the gut for many hours after ingestion. Another factor which may affect absorption from the gastrointestinal tract is the presence of food. This may facilitate absorption if the substance in question dissolves in any fat present in the foodstuff. Alternatively, food may delay absorption if the compound binds to food or constituents, or if it is only absorbed in the small intestine, as food prolongs gastric emptying time. Allied to this is gut motility which may be altered by disease, infection or other chemical substances present, and hence change the absorption of a compound from the gut. Apart from influencing the absorption of foreign compounds, the environment of the gastrointestinal tract may also affect the compound itself, making it more or less toxic. For example, gut bacteria may enzymically alter the compound, and the pH of the tract may affect its chemical structure. The natural occurring carcinogen cycasin, which is a glycoside of methylazoxymethanol (figure 1.1) is hydrolysed by the gut bacteria after oral administration. The product of the hydrolysis is methylazoxymethanol, which is absorbed from the gut and which is the compound responsible for the carcinogenicity. Given by other routes, cycasin is not carcinogenic as it is not hydrolysed. The gut bacteria may also reduce nitrates to nitrites, which can cause methaemoglobinaemia or may react with secondary amines in the acidic environment of the gut, giving rise to carcinogenic nitrosamines.

Conversely, the acidic conditions of the gut may inactivate some toxins, such as snakevenom, which is hydrolysed by the acidic conditions.

The absorption from the gastrointestinal tract is of particular importance because compounds so absorbed are transported directly to the liver via the hepatic-portal vascular system (figure 3.8). Extensive metabolism in the liver may alter the structure of the compound, making it more or less toxic. Little of the parent compound reaches the systemic circulation in these circumstances. This 'first-pass'

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