2. Not the drug activie in the free form only, and this free form may: 1-enters adipose tissue (storage). 2-undergose renal excretion. 3-Binds with target site receptor (pharmacological action). 4-Binds with undesirable receptor (side effect) Generally , [first –pass effect] α [1/bioavaiability(F)]

3. Some drugs (e.g.. lidocaine) are removed so effectively by first-pass metabolism that they are ineffective when given orally. Nitroglycerin is administered buccally to by pass the liver. Some drugs may be given parenterally (eg. IM or IV) for the some reason.

4. 2. Intestinal mucosa (extrahepatic metabolism) Because most drugs are administered orally, the intestine appears to play an important role in the extrahepatic metabolism of xenobiotics. Its importance as follows

5. sulfate conjugation in the intestinal wall (eg. Isoproternol)
sulfate conjugation in the intestinal wall (eg. Isoproternol) *Esterase and lipases present in the intestine may be particularly important in carring out hydrolysis of many ester prodrugs

6. * Bacterial flora present in the intestine and colon appear to play an important role in the reduction of many aromatic azo and nitro drugs (e.g sulfasalazine ) intestinal B-glucuronidase enzymes can hydrolysis glucuronide conugates excreted in the bile, thereby liberating the free drug or its metabolite for possible reabsorption enterohepatic circulation or recycling.