Bioavailability

First Pass Effect

First-pass Elimination

• Transport sequence:

  1. 1.  Across the gut wall into the portal circulation.

  2. 2.  Portal blood transports of the drug to the liver.

  3. 3.  The drug may then reach the systemic circulation.

  4. Bioavailability may be affected by steps 1-3.

  • 4.  Drug metabolism may occur in the intestinal wall or in the blood

  • 5.  Drug metabolism (potentially extensive) may occur in liver

  • 6.  Liver may excrete drug into the bile

  • 7.  Overall process that contributes to bioavailability reduction is the first-pass lost or elimination

• Magnitude of first pass hepatic effect: Extraction ratio (ER)

  • ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour {1500 ml/min})

  • Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER):

    • F = f x (1 -ER)

Extraction Ratios, Routes of Administration, and the First-Pass Effect

• Some drugs that exhibit high extraction by the liver are given orally. 

  • Some examples -- desipramine (Norpramin), imipramine (Tofranil), meperidine (Demerol), propranolol (Inderal), amitriptyline (Elavil, Endep), isoniazid (INH).

• Some drugs which have relatively low bioavailability are not given orally because of concern of metabolite toxicity -- lidocaine is an example (CNS toxicity, convulsions)

• High extraction ratio drugs show interpatient bioavailability variation because all of sensitivity to:

  • Hepatic function

  • Blood flow

  • Hepatic disease (intrahepatic or extrahepatic circulatory shunting)

• Avoiding the first-pass effect:

  • Sublingual (e.g. nitroglycerin)-- direct access to systemic circulation

  • Transdermal

  • Use of suppositories in the lower rectum {if suppositories move upward, absorption may occur through the superior hemorrhoidal veins, which lead to the liver}

  • Inhalation: first-pass pulmonary loss by excretion or metabolism may occur.

Pulmonary Implications: Pharmacokinetics

• Important for uptake of injected/intravenously administered drugs, particularly lipophilic amines (pKa= 8)

• Pulmonary uptake:

  • Effects peak arterial concentration

  • May serve as a reservoir, enabling transport of drug into systemic circulation

• First-pass pulmonary effect magnitude not affected by:

  • Spontaneous respiration

  • Controlled ventilation

  • Apnea

1. Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

2. Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000