Drug metabolism presystemic

As the drug is delivered directly into the bloodstream, this ensures 100% exposure and overcomes problems relating to bioavailability which may occur with other routes, but in particular dosing by the oral route when the drug may be destroyed in the GI tract or metabolized presystemically in the gut wall or in the liver. 

Kemp, D.C., Fan, P.W. and Stevens, J.C. (2002) Characterization of raloxifene glucuronidation in vitro contribution of intestinal metabolism to presystemic clearance. Drug Metabolism and Disposition The Biological Fate of Chemicals, 30, 694—700. 

Mizuma, T. (2002) Kinetic impact of presystemic intestinal metabolism on drug absorption experiment and data analysis for the prediction of in vivo absorption from in vitro data. Drug Metabolism and Pharmacokinetics, 17, 496-506. 

Criteria have been developed to identify and quantify the extent of presystemic metabolism and to indicate when it is occurring. The determination of presystemic metabolism requires only that the systemic availability of a drug is less than the fraction of the dose absorbed. The fraction absorbed may be determined from the urinary excretion of a drug and metabolite after oral administration of a drug relative to that after intravenous administration. Many drugs undergoing presystemic metabolism in humans have been identified on the basis of this type of information. Differentiation between the gut wall and the liver as the site of presystemic metabolism in humans is more difficult, though relatively easy in animals. 

The liver is the most important site of presystemic elimination because of high levels of drug-metabolizing enzymes, its ability to rapidly metabolize different types of drugs, and its unique anatomical location. The following are selected examples of drugs that are subject to considerable hepatic first-pass metabolism the 3-blockers propranolol and metoprolol the analgesics propoxyphene, meperidine, and pentazocine the antidepressants imipramine and nortriptyline and the antiarrhythmic lidocaine. 

Presystemic and systemic metabolism — Presystemic metabolism, which occurs during first-pass metabolism, can decrease the bioavailability of a drug. The following types of metabolism are commonly seen ... 

The two main sources of stereoselectivity in drug disposition are the circulatory proteins and enzymes in both the gastrointestinal tract and the liver. Both binding of drugs to proteins and metabolism by various isozymes are, therefore, often stereoselective. Many examples of stereoselective systemic clearance and presystemic metabolism exist (see Chapters 6 and 7). For a few classes of drugs, metabolism may include chiral inversion (see Chapter 8). This, if unidirectional, adds to the overall stereoselectivity in disposition of drugs. Bidirectional bioinversion (see Chapter 8), on the other hand, similar to chemical racemization (thalidomide, see Chapter 5), may diminish stereoselectivity. 

Pharmacokinetic Definition of Intestinal Absorption (fa), Presystemic Metabolism (Ec and Eh) and Absolute Bioavailability (F) of Drugs Administered Orally to Humans... 

Interestingly, slices of human small intestine also metabolized tegaserod to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism of the drug. 

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