Metabolism of drugs administered orally may occur either by gut wall enzymes or by the liver. Hepatic or gut wall enzymes have a limited capacity and the metabolizing enzymes may not necessarily be distributed evenly in the small intestinal epithelium. Estrone sulphokinases. for example, are more prevalent in the duodenal mucosa than the ileum85. Thus, oestrogens released lower down in the intestine may reach the blood at more rapid rates and in larger amounts, than the same compounds released in the duodenum and jejunum.
With the exception of the mouth and the terminal rectal area, the venous drainage of the gastrointestinal tract drains enters the liver via the portal vein. Thus, a fraction of the active agent undergoes biotransformation by the liver before reaching the systemic circulation and its site of action. Biotransformation generally inactivates drugs, but it can also transform drugs to active metabolites or compounds which have a different pharmacological action to the parent drug, or even to toxic metabolites. Extensive first-pass metabolism, that is inactivation of the parent drug in the liver, is often encountered with lipophilic bases, such as propranolol and amitryptiline, but rarely with lipophilic acids such as salicylic acid and penicillin. The exceptions are esters of lipophilic acids such as acetylsalicylic acid and pivampicillin which, are exclusively metabolized before they reach the systemic circulation86.
Ingestion of food increases the bioavailability of drugs which are metabolized during first pass through the gut wall or liver87. Two mechanisms have been put forward to explain this effect. First, the enhanced splanchno-hepatic blood flow will increase the load of drug delivered to saturable enzyme systems so that a greater proportion escapes metabolism. Second, nutrients may compete for hepatic enzymes so that less drug is metabolized. Concurrent food intake particularly enhances the bioavailability of weak bases, including propranolol, metoprolol, labetalol, and hydralazine, which are metabolized by hydroxylation, glucuronidation and acetylation enzyme systems. It has little effect on the hepatic clearance of those weak bases which undergo presystemic dealkylation such as codeine, prazosin, and dextropropoxyphene88. Food is not expected to influence first-pass metabolism if drugs are given in sustained release preparations because the delivery of drug to the liver is limited by the release of the drug into the gut lumen and not by changes in blood flow.
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