Drug Metabolism Cytochrome P450

236 Pages·4.355 MB·English

by  Glasbergen R., Kozikowski.

Subjects to be covered
(Professor Kozikowski)
• Cytochrome P450, metabolism
mechanisms
• HDACs and Inhibitors – cancer
applications
• Kinases – phosphate transfer, inhibitor
development for cancer – some SAR
studies

Metabolism
• Sum of processes by which particular
substances are handled by the body.
• From the Greek, metabole -- change
Drug Metabolism –
Cytochrome P450
Substrates can undergo a broad range of
reactions during metabolism.
These reactions include, for example,
oxidation, reduction, hydrolysis, hydration,
conjugation and condensation.
Drug metabolism is divided into 2 Phases --
Phase I which are the functionalization
reactions;
And Phase II, which are the conjugation
reactions.
Drug Metabolism
• Foreign organism – elicits antibody
response
• Low molecular weight xenobiotics –
nonspecific enzymes convert them into
polar molecules for excretion
• Enzymatic biotransformations of drugs –
drug metabolism
Principal site of drug metabolism is the liver; also
kidneys, lungs, GI tract
Pathway of Oral Drugs
take via absorbed through small
mouth intestine or stomach
bloodstream
liver
(first metabolized)
Drug metabolism by liver enzymes – first-pass effect
Example of Phase I and II
Phase I Phase II
OH
O-SO H
3
Drug Metabolism
• Drug metabolism is desirable once drug
has reached site of action – may produce
its effect longer than desired or become
toxic.
• Drug metabolism studies are essential for
the safety of drugs. Metabolites must be
isolated and shown to be nontoxic.
Metabolism Studies Can Be a Useful Lead
Modification Approach
Approach:
The antihistamine terfenadine (7.4, R = CH ) was
3
removed from the drug market because of
arrhythmias. Its metabolite fexofenadine (7.4, R =
COOH) is as active, but does not produce
arrhythmias. H C
3
R
HCl
CH
3
HO
N
OH
terfenadine HCl (R = CH )
3
fexofenadine HCl (R = COOH)
7.4
Pathways for Drug Deactivation and Elimination
Rate and pathway of drug metabolism are affected by
species, strain, sex, age, hormones, pregnancy, and liver
diseases.
Drug metabolism is stereoselective, if not stereospecific.
Generally, enantiomers act as two different xenobiotics –
different metabolites and pharmacokinetics.
Sometimes the inactive enantiomer produces toxic
metabolites or may inhibit metabolism of active isomer.
Metabolism of enantiomers may depend on the route of
administration.
For example, the antiarrhythmia drug verapamil is 16 times
more potent when administered i.v. than orally.