BIOTRANSFORMATION Flashcards
WHY DRUG TRANSFORMATION NECESSARY?
• Pharmacologically active organic molecules tend to
be lipophilic and they remain unionized or only
partially ionized at physiologic pH; these are readily
reabsorbed from the glomerular filtrate in the
nephron.
• Certain lipophilic compounds are often strongly
bound to plasma proteins and may not be readily
filtered at the glomerulus.
• Metabolic products are often less
pharmacodynamically active than the parent drug
and may even be inactive.
• However, some biotransformation products have
enhanced activity or toxic properties.
• Therefore, lipid-soluble agents are first metabolized
into more polar (hydrophilic) substances in the liver
via two general sets of reactions, called phase 1
and phase 2.
Phase 1 reactions
usually convert the parent drug to
a more polar metabolite by introducing or
unmasking a functional group (–OH, –NH2, –SH)
If phase 1 metabolites are sufficiently polar
they may be readily excreted.
However, many phase 1 products are not eliminated
rapidly and undergo a subsequent reaction in which
an endogenous substrate such as
glucuronic acid,
sulfuric acid, acetic acid, or an amino acid combines
with the newly incorporated functional group to form
a highly polar conjugate.
hydrazide moiety of isoniazid is
known to form an
N-acetyl conjugate in a phase 2
reaction
Thus, phase 2 reactions may actually precede
phase 1 reactions.
Phase 2 reaction,
this facilitates elimination of the
drug and it can be in the form of conjugation, sulfation, acetylation or methylation.
• Phase 1 involves
Oxidation-Reduction (REDOX
Reaction)
Phase 2 involves
transferases or conjugation
This conjugation reaction usually requires the
substrate to have Oxygen, Nitrogen or Sulfur that
serve as acceptor sites for the hydrophilic moiety,
such as glutathione, glucuronic acid, sulfate or
acetyl
: a drug may undergo Phase 1 via
oxidation, addition of Oxygen. And that Oxygen
would serve as a substrate, where in this component
would be added in replace to the functional group.
What is the importance of biotransformation?
For elimination
What will happen if the drug is not metabolized?
Increase risk for toxicity because the drug
remains in the blood. So, after absorption, it will
be distributed and then metabolize for it to be
excreted.
Phenytoin is highly lipophilic, via Phase 1 reaction
acted upon by
CYT p450
Phenoytin Reaction
converted, and then addition of a functional
group, forming 4-hydroxy-phenytoin. Then after
Phase 1, this phenytoin would be slightly soluble in
water. It would further undergo Phase 2 reaction by
glucuronidation, addition of UGT, where in your
hydroxyl group serves as the substrate. This
metabolite is more water soluble and it can be easily
excreted in the kidney
WHERE DO DRUG BIOTRANSFORMATION
OCCUR?
Liver is the principal organ of drug
metabolism.
If phase 1 metabolites are sufficiently polar
they
may be readily excreted.
The small intestine plays an important role in metabolism since drug that are orally administered absorbed by the GUT and taken to the liver through
the portal vein
FPM
xenobiotic metabolizing enzyme
located
in the epithelial cells of the GI are also responsible
for the initial metabolic process of most oral
medication. So, this should be consider as the initial
site of drug metabolism
Drugs that undergo Substantial FPM
Asprin Glyceral Trinitrate Isosorbide dinitrate Levodopa Lidocaine Metoprolol Morphine Propanolol Salbutamol Verapmil
are more extensively
metabolized in the intestine than in the liver
clonazepam, chlorpromazine, cyclosporine
undergo significant (~50%) intestinal metabolism.
midazolam
First-pass effects may limit the bioavailability of
orally administered drugs (eg., lidocaine) so greatly
that
alternative routes of administration must be used to achieve therapeutically effective blood levels.
Furthermore, the lower gut harbors intestinal microorganisms that are capable of many
biotransformation reactions
Drugs may be metabolized by gastric acid
Penicillin