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Metabolic Changes of Drugs
Prof. Faris T. Abachi ( PHD Pharmacy)
3rd Year Pharmacy
2013
Hydrolytic Reactions
Hydrolyzes (adds water to) esters and amides and their isosteres; the OH from water
ends up on the carboxylic acid (or its isostere) and the H in the hydroxy or amine
■
■
■
Enzymes:
Non-microsomal
hydrolases; however, amide hydrolysis
appears to be mediated by liver
microsomal amidases, esterases, and
deacylases
Electrophilicity of the carbonyl carbon,
Nature of the heteroatom, substituents
on the carbonyl carbon, and
substituents on the heteroatom
influnce the rate of hydrolysis
In
addition,
Nucleophilicity
of
attacking species, Electronic charge,
and Nature of nucleophile and its
steric factors also influence the rate of
hydrolysis
Table: Naming carbonyl - heteroatom groups
R1
R1
R2
Name
Susceptibility
to Hydrolysis
C
O
Ester
Highest

O
C
S
Thioester
C R2
+
O
O
Carbonate
C
N
Amide
O
N
Carbamate
N
N
Ureide
Lowest
The Reactions
O
Ester hydrolysis
R1
O
C
O
R2
R1
C
O
Amide hydrolysis (slower)
R1
C
OH
HO
R2
O
H
N
R2
R1
C
OH
H2N
R2
Carbonate hydrolysis
O
O
R1
O
C
O
R2
R1
HO
+
OH
Carbonate
O
C
O
HO R2
R2
HO
+
Carbonic acid derivative
C
H
OH
O
C
O
+
O
C
O
+
O
H
O
H
Carbonic acid
Carbamate hydrolysis
O
O
R1
O
C
R2
N
R1
OH
+
HO
C
HN
N
+
HO
R3
R3
Carbamic acid derivative
R3
Carbamate
O
R2
R2
C
H
OH
Carbonic acid
Urea hydrolysis
R1
R2
O
N
C
N
R3
R4
Urea derivative
O
R1
R2
NH
+
HO
C
HN
R1
C
+
R3
R4
Carbamic acid derivative
HO
C
H
O
OH
Carbonic acid
O
O
Hydrazide hydrolysis
N
O
R2
R3
H
N
N
Hydrazide
R2
R3
R1
C
OH
+
H2N
N
R2
R3
Hydrazine
C
O
+
O
H
Drug Examples
OH
OH
O
OH
O
+
O
H3 C
OH
H3C
O
O
Salicylic Acid
Aspirin
H2N
H
N
N
CH3
O
CH3
Slow Hydrolysis
Procainamide
H2N
CH3
H2 N
OH
O
N
CH3
O
Rapid Hydrolysis
H
N
N
O
O
CH3
CH3
Procaine
CH3
Lidocaine
CH3
Stereoselectivity of Hydrolysis
 Etomidate (Amidate, hypnotic): R-(+)-isomer is more rapidly hydrolyzed,
but S-(-)-isomer is more rapidly hydroxylated.
The Concept of Prodrugs and Antedrugs
Prodrug
M
D
M
D activation M
D
M
D
Antedrug
D
M
D
M
inactivation
ID
M
= Barrier & ID = inactive drug, D = active drug, M = modifier
(I)
Prodrug: Need metabolic activation
(II)
Antedrug: Active drug that is quickly inactivated thereby minimizing
systemic effects
Prodrugs and Related Terms
■
Albert in 1958 coined the term prodrug to refer a pharmacologically inactive
compound that is metabolically activated in the mammalian system
■
Hard Drugs are not susceptible to metabolic or chemical transformation, have
high lipid solubility and thus accumulation or high water solubility
O
O
S
F3C
N
NH2
O
N
CH3
Celecoxib: t1/2 10-12 h in humans
■
S
F3C
N
NH2
O
N
Cl
t1/2 ca. 680 h (Liver toxicity)
Soft drugs are active compounds that after exerting its action undergo
inactivation to give a nontoxic product. Indeed soft drugs are a group of modified
compounds that are also designed to delivery the drugs in to the brain (the
chemical delivery system). Bodor coined the term.
Basic Concepts of Prodrugs
■
Carrier-linked prodrugs: a pro-moiety is attached, which is not necessary for
activity but may impart some desired property to the drug, such as increased
lipid or water solubility, or site-directed delivery
■
Advantages may include:
■
1.
increased absorption
2.
alleviation of pain at the site of injection if the agent is given parenterally
3.
elimination of an unpleasant taste associated with the drug
4.
decreased toxicity
5.
decreased metabolic inactivation
6.
increased chemical stability
7.
prolonged or shortened action
Bioprecursor prodrugs contain no pro-moiety but rather rely on metabolism to
introduce the functionality necessary to create an active species
O
OH
Cl
H
N
Cl
O
O2N
O
O
O
OH
HO
O
O-Na+
O
ONa
O
Prodrug: Chloramphenicol Hemisuccinate Na Salt
O
Prodrug: Prednisolon Hemisuccinate Sodium Salt
■
Inactive as it is and activated by hydrolysis by plasma esterases to chloramphenicol/
prednisolon
■
Increased water solubility for parenteral administration, which otherwise would
precipitate and cause pain by damaging surrounding tissues
CH
3
OH
N
Cl
H
N
H3 C
Cl
O
CH3
Cl
O OH
O
O2N
H
N
CH3
O
HO
O
O
Prodrug: Chloramphenicol Palmitate
O
S
CH3
(CH2)14CH3
Prodrug: Clindamycin Palmitate
■
Inactive as it is; activated by hydrolysis by intestinal esterases to chloramphenicol/
clindamycin
■
Minimize their bitter taste and improve their palatability in pediatric liquid suspensions
Prodrugs of Functional Groups

Carboxylic acids and alcohols: Most common

Amines and azo linkages: Not been used much

Carbonyl compounds: Not found to be used widely
Carboxylic Acids and Alcohols
Converted to ester prodrugs which are often hydrolyzed to active drug by different types of
esterase enzymes:
Ester hydrolase
Lipase
Cholesterol esterase
Acetylcholinesterase
O
Drug
O
Promoiety
Drug
OH +
O
Drug
HO Promoiety
Esterase
or
Carboxypeptidase
Cholinesterase
O
O
O
Promoiety
Drug
OH + HO
Promoiety
Microflora in the gut
Manipulation of steric and electronic properties of promoiety allows control of rate and
extent of hydrolysis
Advantage of Prodrug Formation I: Increased absorption of hydrophilic drugs by
making less hydrophilic or more lipophilic
H3C
CH3
CH3
OH
O
O
H3 C
O
H
NH+
CH3
OH
NH+
CH3
HO
Esterase
O
CH3
CH3
Dipivefrin
HO
H
Epineprine
H3 C
O
CH3
CH3
OH
Pivalic Acid
Prodrug of Epinephrine: Dipivefrin

More lipophilic, thus achieve higher intraocular concentration

Hydrolysis occur in cornea, conjunctiva, and aqueous humor after
ophthalmic application
Not all carboxylic esters hydrolyzed in vivo where double ester approach is used
H
N
R1
O
S
N
O
CH3
Esterase
CH3
No Reaction
COOR2
(R2 = Ethyl, Propyl, Butyl, Phenyl)
Penicillin Esters
H
N
R1
S
Esterase
O
N
O
R3
COOR2
(R2 = Ethyl, Propyl, Butyl, Phenyl)
Cephalosporin Esters
No Reaction