BIOM 3090 Lecture Notes - Lecture 8: Ramipril, Biotransformation, Active Metabolite
9 Jun 2018
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- Metabolism
o Drug biotransformation or metabolism
o Definition: a change in the chemical structure of an absorbed drug
within a living organism, usually by enzyme-catalyzed biochemical
reactions
▪ Parent molecule acted on some enzyme → makes molecule less
active
o The liver is the main metabolizing organ
▪ All orally administered drugs or other substances are first
taken to liver via portal system
• Can be extensively metabolized before reaching
systemic circulation… called first pass effect
• Reduces bioavailability of drug for target site
• Prevents some drugs from being given orally (e.g.
Lidocaine, many opiods (morphine, fentanyl)
o Why is drug metabolism important?
▪ Enzymes play a pivotal role in metabolism by making drugs
more excretable and terminating their action (inactive)
▪ Many lipid soluble (hydrophobic), weak organic acids or bases
must be metabolized to more water-soluble
(polar/hydrophilic) metabolites
• Polar compounds more readily excreted in urine and
bile
• Excretion of unmetabolized drug may be very slow
▪ While metabolism often results in activation of the compound,
some (few) drugs are activated by metabolism
• Administered as inactive prodrugs
o Improve bioavailability
o Can decrease GI toxicity; can prolong elimination
from the body
o Eg. Eamipril (Altace®) is converted to the active
metabolite ramiprilat by hepatic metabolism
o Why are drugs metabolized?
▪ The liver is the major site of metabolism of xenobiotics (i.e.
foreign or exogenous chemical substance found in body,
including drugs)
▪ Metabolism also occurs in other organs (lungs, GI tract, skin,
kidney, brain, blood plasma)
• GI tract can contribute to first pass effect in addition to
liver
▪ Biotransformation reactions are catalyzed by cellular enzymes
that are located in..
• Smooth ER (most imp)
• Cytoplasm (most imp)
• Mitochondria
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• Nuclear/cell membranes
• Lysosomes
o Isolation of drug metabolizing enzymes for study
▪ Following differential centrifugation of cell homogenaes, drug
metabolizing enzymes are present mainly in..
• Microsomes: vesicles consisting of membranes of ER
which contain membrane-bound Cytochrome P450
enzymes (Phase I enzymes)
• Cytosol: supernatant consisting of cytoplasmic fluid
and soluble Phase II enzymes
o Cell homogenate
o A) Crush and filter: pestle, whole cell
o B) spin at low speed and force: various
organelles
o C) Spin at higher speed and force: pellets of
nuclei
o D) Spin at highest speed and force: lysosome,
mitochondrion
o Fragments of ER and other light particles →
bottom part with the particles if microsomes and
the top is cytosol (fluid)
o How are drugs metabolized?
▪ hepatic enzyme reactions in drug metabolism generally occur
in 2 phases:
• Phase I reactions (oxidation/reduction/hydrolysis
reactions): drugs are converted to more polar
(hydrophilic) metabolites → either excreted or →
undergo phase II reactions
• Phase II reactions (conjugation reactions): reactions
in which a substance from the diet is attached usually to
the functional group derived from phase I reactions →
more polar, excretable product
o some drugs able to undergo Phase II reactions
directly
▪ Characteristics of phase I reactions
• Makes drugs more capable of combining with polar
conjugating groups
• Substrates are lipid-soluble compounds of widely
varied chemical structure
• Metabolites can be more water-soluble, can be
circulated, excreted or undergo a Phase II reaction
• Processes usually involve one or more cytochrome P-
450 (CYP) enzymes found in smooth ER
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