The Principal Organ for biotransformation is the liver, although other organs participate in metabolism. 

• These other systems include lungs, skin, kidney, and the gastrointestinal tract.

Sequence I could be as follows:

1. (1) Oral administration (isoproterenol (Isuprel), meperidine (Demerol), pentazocine (Talwain), morphine)

2. (2) The drug is absorbed intact by the small intestine.

3. (3) The drug is transported to the liver (portal system) where it might be extensively metabolized by the liver, an example of a first-pass effect.

Sequence II might be as follows:

1. (1) Oral administration  (e.g. clonazepam (Klonopin), chlorpromazine (Thorazine)) and

2. (2) The agent is absorbed intact by the small intestine.

3. (3) Extensive intestinal metabolism might ensue, contributing to overall first-pass effects.

Issues in bioavailability:

• Reduced bioavailability might result from several factors including:

  • (a) The first pass effect in which the bioavailability of orally administered drugs become so limited that alternative routes of administration must be employed. 

    • The first-pass effect refers to the drug going to the liver and being metabolized BEFORE it has access to the systemic circulation.  This effect may be very limiting for oral administered drugs.

  • (b) Intestinal flora might metabolize the drug. 

  • (c) The drug itself is unstable in gastric acid; an example of this effect would be penicillin. 

  • (d) The drug might be metabolized by digestive enzymes; an example of this effect would be insulin. 

  • (e) Finally, the drug might be metabolized by intestinal wall enzymes; sympathomimetic catecholamines represent examples of this effect.

• First pass effect:

  • The bioavailability of some orally administered drugs is so limited that alternative routes of administration must be used