Chemical alteration of the drug in a living organism is called biotransformation.

The metabolism of a drug usually converts the lipid-soluble and unionized compounds into water-soluble and ionized compounds.

They are not reabsorbed in the renal tubules and are excreted. If the parent drug is highly polar (ionized), it may not get metabolized and is excreted as such.

Sites: Liver is the main site for drug metabolism: other sites are GI tract, kidney, lungs, blood, skin and placenta.

1.Active drug to inactive metabolite: This is the most common type of metabolic transformation

Phenobarbitone – Hydroxy Phenobarbitone

Phenytoin- P-Hydroxy Phenytoin

2.Active drug to active metabolite

Codeine – Morphine

Diazepam — Oxazepam

3. Inactive drug to active metabolite

Prednisone -Prednisolone

Levodopa- Dopamine

Absorption

• Drug absorption into the systemic circulation from the administration site.

Distribution

• Distribution to the site of action.

Elimination

• Drug elimination from the body.

Additional, commonly used terminology includes:

• Molecular movement (permeation)
• Metabolism
• Disposition is used to describe the combined effects of both metabolism and elimination.

BIOAVAILABILITY FORMULA

• Let’s start with the formula for bioavailability and then illustrate features of each of the variables.

Formula

• F = f x (1 – ER)

Variables

• F = Systemic Bioavailability
• f = Extent of Absorption
• ER = Extraction Ratio

INTRAVENOUS & ORAL ADMINISTRATION: PHYSIOLOGIC DIAGRAM

• To understand what is meant by these variables, let’s diagram the physiology of intravenous absorption and oral absorption, so we can better imagine how various factors influence the bioavailability that comes from these two modes of administration.
• First draw an outline of a human body and establish our target site as an arm muscle.
  • We can imagine a patient who is having painful muscle spasms in the arm and we must get drug to the arm muscle membrane to reduce contractility.
• Draw the heart and show direct arterial circulation to the muscle (the target site).

INTRAVENOUS ADMINISTRATION

• Indicate that we can administer the medication (eg, diazepam) intravenously.
• Show that the venous circulation empties into the heart and then passes into the arterial circulation to reach the target site.
• In this situation, the drug immediately enters the systemic circulation without any barriers or metabolism and so the bioavailability is 100%.
  • 100% of the drug reaches the systemic circulation unchanged.

IV Biovailability

• By definition, IV bioavailability is always 100%.

ORAL ADMINISTRATION (PO)

• Now, let’s address oral bioavailability (we focus on oral administration in this tutorial).

GI absorption

• First, GI absorption. We’ll skip the oral cavity where some absorption can happen via the mucosal membranes and instead draw the stomach, small intestine, and pancreas. These organs are key to GI absorption. Later, we’ll address why the small intestine is so well suited for absorption.

First Pass Effect

• Next, draw a liver and gallbladder and indicate that they are important modulators of bioavailability because of the first pass effect, wherein the drug undergoes hepatic metabolism and gallbladder excretion (we address the extraction ratio formula soon).

Hepatic Portal Vein

• Now, show that the pill is absorbed PO and 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

• Indicate some basic factors that can affect gut absorption:
  • 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.

Oral Bioavailability

• Let’s summarize some key factors we can visualize in bioavailability:
  • Gut absorption
  • First pass effect
  • Hepatic portal blood flow
• Oral bioavailability is wide-ranging; from minimal bioavailability (5%) to great (95%).
  • For diazepam (Valium), there is ~ 98% PO bioavailability, thus we administer a similar dose orally as we do IV (eg, typically 5-10 mg IV or PO) because the bioavailabilities are roughly the same.
  • The main difference is the time of action: IV administration takes 5-10 minutes whereas oral administration takes 1-2 hours.

EXTRACTION RATIO (THE FIRST PASS EFFECT)

Extraction Ratio (*The First Pass Effect*)

• Let’s see how we can quantify the affect of liver metabolism, gallbladder excretion, and hepatic portal flow with the extraction ratio.
  • Metabolism refers to the activation and deactivation of drugs, as well as their generation of active metabolites. (See Nitrogen Handling Tutorial).

Extraction Ratio Formula

• ER = CL(liver)/Q
  • 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. We address this in detail in our Pharmacokinetics Calculations tutorial.