Farmaceutická chemie I. 2. rok studia
Metabolismus léčiv.
Doc. PharmDr. Oldřich Farsa, Ph.D.
Drug metabolism or biotransformation
● reactions that are responsible for the conversion of drugs or
other xenobiotics into another products (metabolites) within the
body before and after they have reached their sites of action
● it usually occurs by more than one route
● their end products are normally pharmacologically inert
compounds that are more easily excreted than the original drug
● classified for convenience as Phase I reactions which either
introduce or unmask functional groups that are believed to act
as a centre for Phase II reactions; product of Phase I are often
more water soluble and so more readily excreted than the
parent drug
● Phase II reactions produce compounds that are often very
water soluble and usually form the bulk of the inactive excreted
products of drug metabolism
Schematic of biotransformation phases
PHASE I redox metabolism enzymatic
apparatus
Mixed-Function Oxidases, formed by
microsomes made out of smooth endoplasmic
reticulum (SER) folded over on itself.
• Cytochrome-P450 Enzyme Complex: Has
four required components in order to work.
• Cytochrome-P450 Enzyme
• Cytochrome-P450 Reductase
• O2
• NADPH: NADPH is the only energy source.
Types of Phase I reactions
OXIDATIVE REACTIONS: on drugs, such as aromatic
hydroxylation, aliphatic hydroxylation, N-dealkylation, Odealkylation,
S-dealkylation, N-oxidation, S-oxidation,
desulfuration etc. in most on CYP.
REDUCTIVE REACTIONS: azo, nitrile, carbamyl
HYDROLYTIC REACTIONS: ester hydrolysis, amide
hydrolysis.
OTHER REACTIONS: decarboxylation
ibuprofen
C O 2 H C O 2 H
H O
Aliphatic ω−hydroxylation: ibuprofen (NSAID)
Aliphatic (ω−1)−hydroxylation: pentobarbital (hypnotic, sedative ...)
H N
N
O
O
H
O
H N
N
O
O
H
O O H
pentobarbital
antiepileptic phenytoin: aromatic hydroxylation and water addition
Arene epoxide intermediate produces multiple products
N
N
O
C Y P 2 C 8 ,9 N
N
O
O
H
H
H Y L 1
p h e n y t o in
3 ,4 - d ih y d r o d
ih y d r o x y p h e n t o in
N
N
O
H O
N
N
O
O H
N
N
O
H O O H
p a r a - h y d r o x y p h e n y t o in m e t a - h y d r o x y p h e n y t o in
O
N
O H
H
O
N
O H
H
O H
O
N
O H
H
O H
β-adrenolytic – anti-hypertensive propranolol: hydroxylation in 2 positions of
naphthalene ring
CYP3A4
terfenadine
(Seldane – not authorized in CZ)
fexofenadine
(Ewofex ® )
•cardiac adverse effects not present
NH O
O H
NH O
C O 2 H
O H
Metabolism of terfenadine: oxidation of one of methyls of tert-butyl into carboxyl
●H1
-antihistamine if the 2nd
generation developed in 1980th
●serious cardiac adverse effects including TdP arrythmias
N (or O, S)-oxidative dealkylation
R N
C H 2
C H 2
R
C H 2
O H
R N
C H 2
C H 2
R
C H 2
R N
C H 2
C H 2
R
C H 3
R N
C H 2
C H 2
R
C H 3
+
O 2
- H +- 1 e H
C H O+
R N
C H 2
C H 2
R
H
N-demethylation generates formaldehyde
Oxidative N-demethylation: ethylmorphine (antitussive)
OO O H
N
C H 3
OO O H
N
H
H C H O+
e t h y lm o r p h in e d e s m e t h y l- e t h y lm o r p h i n e
N-demethylation favored over O-deakylation
Oxidative desisopropylation: propranolol
O
N
O H
H
O
N
O H
H
O H
O
N
O H
H
O H
O
N
O H
H
H
- CH3
COCH3
Oxidative S-demethylation: 6-methylthiopurine = 6-methylsulfanylpurine
N
N
N
N
S
C H 3
N
N
N
N
S H
H C H O+
6-methythiopurine
●prodrug
●not used
6-mercaptopurine
●active form normaly
originated from
antineoplastic and
antirheumatic
azathioprin
PHASE I hydrolytic metabolism enzymatic
apparatus
● hydrolases
● esterases – have also some amidase activity
– cholinesterases: acetylcholiesterase, butyrylcholinesterase
– pseudocholinesterase
– lipases
● peptidases – naturally cleave the peptidic bond, but are
capable to cleave also other amide bonds
– exopeptidases – cleave peptide bonds of terminal amino acid
rests
● carboxypeptidases – from C-terminal
● aminopeptidases – from N-terminal
– endopeptidases – cleave peptide bonds inside peptide chain
● in general are all the types of peptidases capable to
cleave anilides, naphtylamides etc.