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Drug Metabolism and Prodrugs
Drug metabolism is the transformation of
foreign compounds ( xenobiotics) into
water soluble derivatives which can easily
eliminate via renal route.
Xenobiotics
( non essential exogenous, foreign compounds )
• This applies particularly to chemical compounds
which enter the organism and don't serve as
nutrient or other essential factors.
• Xenobiotics can not be allowed to concentrate
beyond limits in a living system, but must be
eliminate by excretion.
• Drug metabolism may be regarded as
detoxification processes in some cases.
• Not all metabolites are non toxic
Example
As a rule, the metabolism of xenobiotics
takes place in two steps known as phase I &
phase II reactions
Phase I ( functionalization reaction
)
Is the process of increasing of the hydrophilicity
of lipophilic drug by introducing polar
functional group eg; oH,cooH,NH2,SH to the
molecule through oxidative reductive &
hydrolytic biotransformation.
Phase II ( conjugation reactions )
• Link an endogenous solubilizing moiety either to the
original drug (if polar function are already present)
or to the phase I metabolite.
• Common solubilizing groups are glucuronic acid,
various amino acids or sulphate groups.
• The conjugate molecule, being more polar and
water-soluble, is usually excreted via the renal
route
Effect of metabolism on the
therapeutic activity of drugs
Conclusion
• Drug metabolism or biotransformation are the
chemical reactions that are responsible for the
conversion of drugs into other products within the
body before and after they have reached their sites of
action.
• Almost all of these reactions are enzyme catalyzed.
• A knowledge of the concepts of drug metabolism is
useful in both the design of new drugs and the
improvement of existing drugs.
Factors affecting drug metabolism
•
•
•
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Genetic factors
Physiological factors
Pharmaceutical factors
Drug interactions
Genetic factors
Biological half –life (t1/2) of various drugs
Physiological factors
eg: Age which is the ability of the body to metabolize the drug lower in
v. young & eldery.
Pharmacodynamic factors
•
The dose, the route and the frequency of
administration of drugs can affect their
metabolic profiles.
• Drugs given too frequently may overload
the metabolic system available to it,
leading to elevated blood and tissue levels
of the drugs. The effect of protein binding
also influences the metabolism
Drug interactions
• Phenobarbital stimulate the metabolism of
Diphenylhydantoin.
• The half life of Chloropropamide,
Diphenylhydantoin & Cyclophosphamide is
increase in presence of Chloramphenicol.
• Plasma Concentration of anticoagulants
such as Warfarin are reduced by
simultaneous application of barbiturate
Phase I (Functionalization
reactions
• Oxidations (electron removal,
dehydrogenation and hydroxylation)
• Reduction ( electron donation, hydrogenation
and removal of oxygen )
• Hydrolytic reactions of amide & ester.
Oxidation Reactions
• The main enzymes involved in the
oxidation of xenobiotics called mixed –
function oxidases or monooxygenases,
found mainly in the liver but also occur to
less extent in other tissues.
• Cytochrom P-450 ( CYP – 450 )
Simplified Cytochrome P450 Redox Cycle
Major reactions of oxygenation
catalyzed by cytochrome P450:
1-Carbone oxidation reaction: 2-N-Oxygenation
reactions.
a)Hydroxylation of Saturated aliphatic C atom.
b)Hydroxylation of aromatic ring.
c)Oxidation of unsaturated aliphatic system.
Major reactions of oxygenation
catalyzed by cytochrome P450
Oxidation reactions
1.
Carbon oxidation reaction
abcd-
Hydroxylation of saturated aliphatic carbon atoms
Hydroxylation at activated SP3 carbon atoms
Oxidation attack on unsaturated aliphatic systems
Hydroxylation of aromatic rings
2.
N-oxygenation reactions
3.
S-oxidation reactions
Hydroxylation of saturated aliphatic
carbon atoms
• Saturated aliphatic C-H bonds are normally
metabolised by hydroxylation ( ω & ω-1 )
Enzymatic introduction of a hydroxyl group into
cyclohexane ring generally occurs at C-3 or C-4
In human the trans-4-hydroxycyclohexyl product
has been reported as a major metabolite of
acetohexamide ( hypoglycemic agent )
Terodiline
Aromatic p-hydroxylation predominate with Risomer where as benzylic hydroxylation is
preferred with S-isomer.
Hydroxylation at activated SP3 carbon
atoms
Oxidation involving carbo-heteroatom
system:
N,O,S func.gp are commonly found in most drug
&foreign comp.
metabolic oxid. of C-N & C-S involve hydroxylation of
alpha carbone atom attached directly to
heteroatom(N,O,S)
N-dealkylation:
oxidative alpha-hydroxylation at alpha-C then dealkylation.
Halogenated aliphatic derivatives
Oxidation attack on unsaturated
aliphatic systems (alkene epoxidation).