Pharmacology 3620 Lecture Notes - Lecture 4: Drug Metabolism, Grapefruit Juice, Chemical Polarity
1 May 2018
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Lecture 004: Drug Metabolism
Objectives
● Name the major drug elimination mechanisms and organs of elimination.
● Describe the relevance of drug metabolism to elimination, pharmacological effect and
toxicity.
● Define Phase I and Phase II metabolism.
● Describe the basic biochemistry of the CYP enzymes.
● Name the most important human drug metabolizing enzymes.
● Describe how grapefruit juice interacts with common medications.
● Describe the major pathways, enzymes and reactions for Phase II drug metabolism.
Elimination Mechanisms of Drugs
● Metabolism: 70%
● Renal: 20%
● Biliary: 5%
Role of Phase I and II Enzymes in Drug Elimination
● Removal of drugs from systemic circulation by making lipophilic molecules more polar to
promote their excretion
● Phase I: Oxidative
○ Introduction/exposure of a functional group on the substrate
○ Ex. adds an -OH (which is like a handle)
● Phase II: Conjugative
○ Adding a (large) polar substrate to the functional group so
the overall molecule is hydrophobic
○ Often, adding the “handle” in Phase I is what allow Phase II
enzymes to recognize the substrates
■ Allows it to be conjugated with the polar molecule
● Often (not not always) Phase I precedes Phase II
○ can have Phase II metabolism without Phase I.
Drug Metabolism
● The chemical conversion of a molecule (the drug) to another (the metabolite)
● Why do we metabolize drugs?
○ Get get rid of them from circulation
○ Conversion of the hydrophobic molecule to hydrophilic ones allows for easier
urinary excretion
● Most metabolites are more hydrophilic than their parent drug
○ Thus they are easier to eliminate from the body
● Most metabolites are pharmacologically inactive
○ No drug activity
● Sometimes, however, the metabolite remains active
○ Can have the same,more or less activity as the parent drug
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Document Summary
Name the major drug elimination mechanisms and organs of elimination. Describe the relevance of drug metabolism to elimination, pharmacological effect and toxicity. Define phase i and phase ii metabolism. Describe the basic biochemistry of the cyp enzymes. Name the most important human drug metabolizing enzymes. Describe how grapefruit juice interacts with common medications. Describe the major pathways, enzymes and reactions for phase ii drug metabolism. Role of phase i and ii enzymes in drug elimination. Removal of drugs from systemic circulation by making lipophilic molecules more polar to promote their excretion. Introduction/exposure of a functional group on the substrate. Ex. adds an -oh (which is like a handle) Adding a (large) polar substrate to the functional group so the overall molecule is hydrophobic. Often, adding the handle in phase i is what allow phase ii enzymes to recognize the substrates. Allows it to be conjugated with the polar molecule. Often (not not always) phase i precedes phase ii.
