Extraction Ratio (The First Pass Effect)
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*Extraction Ratio (The First Pass Effect)**
Overview
- The liver and gallbladder are important modulators of bioavailability because of the first pass effect, wherein the drug undergoes hepatic metabolism and gallbladder excretion.
Hepatic Portal Vein
- When pill is absorbed orally (PO), it passes via the hepatic portal vein through the liver and then via the inferior vena cava into the heart.
- From there it will reach to the target site via arterial circulation (like the IV administration).
- Thus, hepatic portal circulatory issues will affect drug delivery to systemic circulation.
Gut Absorption Factors
- Gastric emptying will effect drug delivery to the small intestine and thus affect pharmacokinetics.
- GI blood flow will impact pharmacokinetics.
- Stomach pH impacts drug diffusion across membranes (we'll see why later)
- Interactions between the drug and other drugs and inert substances will impact its absorption.
Extraction Ratio
Formula
- ER = CL(liver)/Q
Variables
- ER = Extraction Ratio
- Q = Hepatic (liver) blood flow
- CL(liver) = Liver clearance
Extraction Ratio and Bioavailability
- We see that the greater the liver clearance, the higher the extraction ratio.
- The higher the extraction ratio, the lower the percentage of systemic bioavailability.
Circumventing the First-Pass Effect
- We can circumvent the first-pass effect via alternative administration routes:
- Sublingual
- Transdermal
- Rectal suppositories
- Inhalation (however there is pulmonary extraction with first-pass loss)
Distribution
- Distribution refers to several determinants, such as how body organ characteristics, for instance their size, blood flow uptake, lipid vs aqueous cellular makeup effect drug delivery.
- As well, it references how the concentration of macromolecules (eg, albumin) effect drug delivery.
- And it covers an important, commonly clinically cited value: the volume of distribution (Vd), which predicts the ratio of drug that will distribute to body tissue vs blood plasma.