Liver first-pass metabolism

Sequential gut mucosal and liver first-pass metabolic extraction... 

Bioavailability is the other important conceptual pharmacokinetic parameter, in addition to clearance. The key concepts are summarised in Box 5.3. Bioavailability is defined as the proportion of an administered dose that reaches the systemic circulation . It has no units and is usually expressed as a percentage. Values range from 0 to 100%, and will be 100% or complete for an intravenously administered drug. After oral administration, only a proportion of the drug may reach the systemic circulation because of incomplete absorption or because absorbed drug may be metabolised in the gut wall or liver (first-pass metabolism). For... 

Alteplase was the first commercially available recombinant tissue-type plasminogen activator (rt-PA) (25), It has a plasma half-life of less than five minutes and is metabolized by the liver, This agent was initially hailed as fibrin-specific unlike its precursors (urokinase and streptokinase). It was thought that this would result in a better safety profile, but this has not been born out in either the coronary or the peripheral experience, where actually there may be a higher bleeding risk as infusion time increases. Alteplase is currently indicated for use in the treatment of myocardial infarction, acute ischemic stroke, and pulmonary embolism. 

A major fate of PA is conversion to DG that can be metabolized to PC, PE, and TG (Fig. 1). Alternatively, PA can react with CTP to form CDP-DG that is utilized for biosynthesis of the inositol phospholipids as well as phosphatidylglycerol (PG) and diphosphatidylglycerol (DPG) (Fig. 1). Inositol is a cyclohexane derivative in which all six carbons contain hydroxyl groups. The most common inositol isoform is myo-inositol but other less abundant inositols with different structures also occur. The first report of an inositol-containing lipid was in 1930 in Mycobacteria which is ironic since inositol lipids are rarely found in bacteria. Brain is the richest source of inositol-containing lipids, as first discovered by Folch and Wooley in 1942. In 1949, Folch described a PI phosphate (PI-P) that was later found to include PI and PI bisphosphate (PI-P2). The chemical structures of PI, PI-P, and PI-P2 were determined by Ballou and co-workers between 1959 and 1961. PI (1.7 pmol/g liver) constitutes -10% of the phospholipids in cells and tissues. PI-P and PI-P2 are present at much lower concentrations (1-3% of PI). In 1958, Agranoff and co-workers first reported the incorporation of [ HJinositol into PI. Subsequently, Paulus and Kennedy showed that CTP was the preferred nucleotide donor. 

PAs themselves show a more or less low acute toxicity but in vivo they undergo a three-step metabolic toxication process in the liver, which is, as a result, the first target organ for the toxicity. 

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