Drugs are primarily metabolized in the liver and gastrointestinal tract and then excreted through the kidneys. Water-soluble drugs are readily excreted by the kidneys, but fat-soluble drugs tend to accumulate until they are converted into water-soluble compounds or metabolized by the liver into inactive compounds. After absorption from the gastrointestinal system, these drugs pass through the liver prior to entering the systemic circulation where they undergo first-pass metabolism in the liver and intestinal wall. Hepatic metabolism may be either phase I or phase II metabolism (Buxton 2006).

Phase I metabolism, which involves oxidation via the cytochrome P450 mono-oxygenase system, reduction, or hydrolysis, prepares the drug for excretion or further metabolism by the phase II pathways. Phase II metabolism consists of conjugation of the drug or its metabolites with hydrophilic compounds in the glucuronidation, acetylation, or sulfation pathways. This produces a form of the drug that is more readily excreted. First-pass metabolism can result in significant changes in the activity of a medication and may explain why there is often a significant difference in potency when medications are given parenterally rather than orally.

Hepatic metabolism may be limited by the blood flow that delivers the drug to the hepatic metabolizing enzymes as well as the intrinsic capacity of the enzymes involved in metabolism. Hepatic blood flow may be altered in liver disease due to portosystemic shunting and may be increased in chronic respiratory illness, acute viral hepatitis, and diarrhea and in conjunction with certain medications (e.g., clonidine). In practice, however, only severe cirrhosis has clinically significant effects on hepatic blood flow. Hepatic metabolism is also affected by enzyme inhibition or induction caused by specific medications. Although hepatic diseases, such as acute viral hepatitis, may limit phase I metabolism, liver disease generally does not have clinically significant effects on glucuronide conjugation reactions due to its large reserve of enzymes.

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