Pharmacology 3620 Lecture Notes - Lecture 2: Portal Vein, Plasma Protein Binding, Bioavailability
1 May 2018
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Lecture 002: Drug Absorption and Distribution
Objectives
● Define bioavailability and first-pass effects as it pertains to drugs absorption
● Describe how a drug’s bioavailability is measured
● Describe the factors affect drug distribution in the body
● Define the pharmacokinetic parameter, volume of distribution and describe how a
drug’s volume of distribution is measure
● Describe the capillary barriers to drug distribution
● Describe the role of plasma protein binding on drug distribution
Drug Absorption
● Absorption is the transfer of drug from its site of administration to the bloodstream
(systemic circulation)
○ Many drug target requires the drug to get into circulation for it to take effect
● Drug absorption RATE and EXTENT depends on
○ Absorption rate
■ How quickly the drug moves from the site of administration to circulation
○ Extent of absorption
■ How much of the dose gets into circulation
○ Absorption environmental factors
○ Drug’s chemical characteristics
○ Route of administration
■ Drugs can be taken in many ways
■ Oral administration
● Most common route of administration
● Extent of intestinal drug absorption impacts the dose of many
drugs
■ IV administration
● Drug is injected directly to the vein
● Extent of absorption is 100% (All of the dose is reach the body)
● No other route is like this
Factors Affecting Intestinal Drug Absorption
● G
astrointes
tinal tract
● S
mall
intestine
is most
important
for drug
absorptio
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n
○ Has many folds and microscopic folds (villi, microvilli)
■ Much greater SA than a simple tube
● Chemical Stability
○ Some drugs are susceptible to stomach acids
○ pH varies along length (stomach pH = 1-2, small intestine pH = 3-8)
● Tablet additives
○ Sometimes can interfere with the absorption of the drug
Definitions
● Bioavailability (F)
○ Proportion (%) of the drug dose that reaches systemic circulation in an
unaltered form after the drug is administered
○ Pharmaceutical term that describes absorption
● First-pass effect
○ Major determinant of bioavailability
○ Drug can be metabolized by the gut/liver during the initial absorption of an oral
dose before it can reach systemic circulation (lowers F)
Bioavailability and First-Pass Effect
● Intestine lumen (enterocytes)
○ Drug must pass through to get to the
portal vein
○ 1st first-pass organ
● Portal vein -> liver
○ 2nd first-pass organ
● However, the intestines and liver are major
metabolizers of drugs
○ Reduces the drug that actually gets to
the blood
Felodipine and the First-Pass Effect
● A drug that lowers blood pressure
● 70% of the drug is metabolized by the enzyme in the enterocytes of the small intestine
● 30% enters the portal vein
● 50% of the drug is metabolized by the enzyme in the liver
● Because of the metabolization that happened in the intestines and liver the overall
bioavailability is 15%
○ 1 x 0.7 x 0.3 x 0.5 = 0.15
Estimating the bioavailability of an orally administered drug
● Bioavailability is calculated by comparing the area-under-the-curve (AUC) of blood
concentration vs time plots after a single IV bolus and oral dose
○ AUC is sometime called “exposure”
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■ Parameter that takes into account the magnitude of drug concentration
and the duration of drug levels
● Experiment to determine bioavailability (F) of a drug
○ Inject a drug by IV
■ Take blood samples and measure the concentration of the drug over time
■ Makes a fairly straight line when graphed
■ This is considered to be the 100% bioavailability
○ Wait a few weeks for the drug to leave the body completely
○ Oral administration of the drug
■ Take blood samples and measure the concentration of the drug over time
○ To determine bioavailability calculate the RATIO of the AUC of the oral dose to
the IV bolus
■ F = AUCoral/AUCIV x 100%
Examples of Oral Bioavailabilities
● Alendronate
○ For osteoporosis
○ F = 0.6%
● Vitamin C
○ F = 98% - 10%
■ Not a constant, depends on the dose
○ Higher when given a low dose
○ Variability exist because vitamin C requires drug transporters in the GI for
absorption
■ Those transporters can be saturated (when given a high enough dose of
vitamin C)
● Warfarin
○ Blood thinner
○ F = 100%
Generic vs Brand Name
● Generic drugs have same amount of drug but manufactured in a different way
● Usually cheaper
○ Used by most people because it lowers health care cost
● Must be approved by Health Canada for marketing
○ Must have the same quality of ingredients as brand name drug
● Health Canada ask the companies to test for Relative Bioavailability
○ Bioavailability in the generic drug must be similar to the brand name in both
availability and rate
○ Test by giving a person the brand name and generic name and measuring the
concentration of the drug over time
○ Compare the two AUCs after
■ 2 AUCs must be within 85%-125% to be approved by Health Canada
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Document Summary
Define bioavailability and first-pass effects as it pertains to drugs absorption. Describe how a drug"s bioavailability is measured. Describe the factors affect drug distribution in the body. Define the pharmacokinetic parameter, volume of distribution and describe how a drug"s volume of distribution is measure. Describe the capillary barriers to drug distribution. Describe the role of plasma protein binding on drug distribution. Absorption is the transfer of drug from its site of administration to the bloodstream (systemic circulation) Many drug target requires the drug to get into circulation for it to take effect. Drug absorption rate and extent depends on. How quickly the drug moves from the site of administration to circulation. How much of the dose gets into circulation. Drugs can be taken in many ways. Extent of intestinal drug absorption impacts the dose of many drugs. Drug is injected directly to the vein. Extent of absorption is 100% (all of the dose is reach the body)
