BPS 2110 F15 Metabolism
BPS 2110 F15 Metabolism
BPS 2110 F15 Metabolism
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The CYP- family of enzymes
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Metabolism
• Introduction of an OH group at a saturated carbon
atom
• Mechanism -1 :
– 1. Abstraction of a hydrogen atom, preferred from a relatively weak C-
H bond, thereby forming a relatively stable carbon centered radical
– 2. Reaction with molecular oxygen to form a hydroperoxy radial
– 3. Abstraction of a hydogen atom from another molecule giving a
hydroperoxide
– 4. Reduction of the hydroperoxide to an alcohol.
.
H .H O HO
C
H . C O2
O O
H -H C H CH2-OH
H C H
H H
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• Introduction of an OH group at a saturated carbon
atom (sp3 hybridized)
• A key part of the active site in the Cytochrome enzymes is the
iron center (Fe+2)
• Reaction with oxygen to form an Fe- hydroperoxy radical
2 3
step 1 Fe + O O Fe
O
O
• Abstraction of a relatively weak C-H bond from the substrate
to form Fe-hydro-peroxide and a carbon centered radical
3 3
+ H R
step 2 Fe Fe +R
O O
O O
H
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CYP mediated oxidation at sp3 carbon
• Overall
CYP
H R R-O-H
O2
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Chemistry: C-H bond dissociation energies
• Bond strengths
H
H H Primary C-H bond ~ 98 Kcal/mol
C
H 3C C C H Seconday C-H bond ~ 95 Kcal /mol
H 3C H H
Tertiary C-H bond ~ 91 Kcal mol
C C C
C > C > H
C H H
Tertiary radical > secondary radical > primary radical
H
-H H -H H H
H
H H H
Benzylic radical allylic radical
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Oxidation at an allylic, or benzylic position is often
preferred. Why?
Possible monohydroxylation products
H H H H H H H OH H OH H H H H H H
C C CYP450 C C C C C
CH 3 CH 3 CH 3 CH 3
C H C H H C H
H H H H H H H OH
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Demethylation of R2N(CH3) to R2N-H
Demethylation of R-O-CH3 to R-OH
H (+) O
CH 3 H2 H
N P450 C
C H H N
N O H
O2
H (+) H
O
O O H O
O P450 C
CH 3 CH 2 H H
O2
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Demethylation of R2N(CH3) to R2N-H
Demethylation of R-O-CH3 to R-OH
H2
. H
.
H
OH
-H N
C H N H
N H
O
. O H
.
C H -H O H
H2 OH
H
H
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Metabolism: Introduction of OH groups into
aromatic rings
R R
P450
O2 O
H
H O H
O O-H
H
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Effect of substituents on aromatic
hydroxylation
• If the aromatic ring acts as a nucleophile
• A substituent on the ring that is electron donating {EDG} will increase its
reactivity
EDG increased reactivity towards electrophiles
OR
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EWG groups reduce the rate of metabolism
drugs containing a benzene ring.
• In many drugs with aromatic rings have EWG substituents
are introduced in order to slow down their rate of
metabolism and increase their half-life in the body. (Other
effect of F and Cl: increase in lipophilicity [logP])
Celebrex Lipotor
F
O
N
H OH OH O
SO2 NH2
N H
N O
N
F3 C
Cl
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Metabolism at aromatic rings other than
benzene
• Electron poor aromatic rings tend to be metabolically more
stable than a benzene ring
N
Decreasing electron density
N N
Increasing metabolic stability
benzene pyridine pyrimidine
Explanation .. Electrophile
N N
H H
pyrrole
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Drug-Drug Interactions
• Many drug- drug interactions are due to
metabolism issures
• Need to be aware of the
– Metabolism (enzyme involved)
– The degree of inhibition and
– Therapeutic Index [TI] of the drug.
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Therapeutic Index (TI)
• Toxic Dosage for 50% of patients / Therapeutic
Dosage for 50 % of the patients
• Or TD50/ED50
• Ideally a large number: low toxicity relative to
effective dosage
• If less than 5 it gives a narrow window and a small
margin of error for safety
• Digoxin, for coronary heart disease has a rather small
TI
• Acetominiphen has a large TI, a relatively safe drug
• Many cancer drugs have rather small TIs !!! Why?
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Liver metabolism
• Avoiding liver enzyme metabolism - also
called “first pass metabolism”
• Oral administration: Drugs are absorbed
through the gut, go to the liver;
– Oxidative metabolisms occur mainly in the liver
and gut
– To avoid this have the drug go into the blood
stream and before it can be metabolized by liver
enzymes.
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Methods of administration
• Oral – most common, reasonable compliance
• Intravenous injection typical of many anti-cancer
drugs, often problems with formulations
• Intramuscular injection –most vaccines, acid
sensitive penillins
• Sublingual - angia drugs –nitoglycerin
• Rapid absorption into the blood, rapid action
(KCN)
• Inhalation- asthma drug –salbutamol “puffer”
• Transdermal- hormones, nicotine patch
• Rectal suppositories –aspirin
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• Examples
– Nitroglycerin = anti-anginal
– Aspirin = analgesic
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