11/0 9/2 0 12

N y i M e k a r S a p ta r in i

A b s o r p t io n , D is t r ib u t io n ,
M e t a b o lis m a n d E x c r e t io n

A b s o r p t io n d e p e n d s o n th e r o u t e o f

a d m in is t r a t io n

D r u g d is tr ib u tio n d e p e n d s o n h o w

s o l u b l e th e d r u g m o l e c u l e is in fa t ( t o
p a s s th r o u g h m e m b r a n e s ) a n d o n
th e e x t e n t to w h ic h th e d r u g b in d s to
b lo o d p r o t e in s ( a lb u m in )

D r u g m e ta b o lis m

is a c h e m i c a l
tr a n s f o r m a t i o n o f d r u g in t o it s
m e ta b o lite s

D r u g e l i m i n a t i o n is a c c o m p l i s h e d b y

e x c r e t i o n in t o u r i n e a n d / o r b y
in a c t i v a t i o n b y e n z y m e s in th e li v e r

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M E T A B O L IS M
M e t a b o l i s m is th e e n z y m a t i c c o n v e r s i o n
o f o n e c h e m i c a l c o m p o u n d in t o a n o t h e r .
M o s t d r u g m e t a b o l i s m o c c u r s in th e li v e r ,
a l t h o u g h s o m e p r o c e s s e s o c c u r in t h e g u t
w a l l , lu n g s a n d b l o o d p l a s m a .
 O v e r a ll, m e ta b o lic p r o c e s s e s w ill c o n v e r t
t h e d r u g in t o a m o r e w a t e r - s o l u b l e
c o m p o u n d b y in c r e a s i n g it s p o l a r i t y . T h i s
is a n e s s e n t i a l s t e p b e f o r e t h e d r u g c a n
b e e x c r e t e d in t h e b o d y fl u i d s s u c h a s
u r in e o r b ile . O n ly a fe w d r u g s c a n b e
e x c r e t e d w ith o u t b e in g m e ta b o lis e d fir s t

O n th e w h o le , a s d r u g s a r e
m e ta b o liz e d th e ir th e r a p e u tic
e ffe c t d im in is h e s .

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W h e n d r u g s e n t e r th e b o d y , th e y a r e
s u b je c t to a t t a c k fr o m a r a n g e o f
m e t a b o lic e n z y m e s . T h e r o le o f th e s e
e n z y m e s is to d e g r a d e o r m o d i f y th e
fo r e i g n s t r u c t u r e , s u c h th a t it c a n b e
m o r e e a s ily e x c r e te d .

D ru g
a s th
body
of su

If th e d r u g is p o l a r, it w i l l b e q u i c k l y
e x c r e t e d b y th e k id n e y s . N o n - p o la r
d r u g s a r e n o t e a s ily e x c r e te d .

T h e p u r p o s e o f d r u g m e t a b o l i s m is to
c o n v e r t s u c h c o m p o u n d s in t o m o r e
p o la r m o le c u le s th a t c a n b e e a s ily
e x c re te d .

s a r e fo r e ig n s u b s t a n c e s a s fa r
e b o d y is c o n c e r n e d , a n d th e
h a s it s o w n m e t h o d o f g e t t i n g r i d
c h c h e m i c a l in v a d e r s .

FA K T O R YA N G
M E M P E N G A R UH I
M E T A B O L IS M E :
1 . F a k to r fis io lo g is
a . P e r b e d a a n s p e s ie s
b . F a k t o r in d iv id u
Um u r
Je n i s k e l a m i n
K e h a m ila n
K e a d a a n g iz i
R itm e b io lo g is

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2 . F a k to r p a to lo g is
a. P e n u ru n a n e fe k o b a t
b . P e n in g k a ta n e fe k o b a t
3 . F a k t o r lin g k u n g a n
a. m a k a n a n
b . C e m a r a n u d a r a d a n a ir
c . K o n d is i lin g k u n g a n ( s u h u
& k e le m b a b a n )
d . S tr e s s d a n k e le la h a n

S ite s o f d r u g s
m e t a b o lis m
L iv e r
G I tr a c t : g u t b a c te r ia &
p ro te a s e s
 In te s tin a l w a ll, e .g .
c h lo r p r o m a z in e
 P la s m a : e s te r a s e s , e .g .
a c e ty ls a lic y la te
 S p e c ia lis e d tis s u e s :
m o n o a m i n e o x i d a s e s in
n e r v e e n d in g (e .g .
n o r a d r e n a lin e

a d r e n a lin e )



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IM P O R T A N C E O F
D R U G M E T A B O L IS M

S k e m a m e t a b o lis m e
obat

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S ir k u la s i
e n te ro h e p a tik


B b r p o b a t & m e ta b o lit y g
d ie k s k r e s ik a n k e d lm
e m p e d u k e m b a li m a s u k
k e d lm s is te m s ir k u la s i m ll
re a b s o rp s i d a ri ro n g g a
usus
O b a t y g d ie k s k r e s i k e d lm
e m p e d u s b g b e n tu k
k o n ju g a t g lu k u r o n id a ,
s u lfa t a ta u g lu ta tio n m r p
s a s a r a n a r il s u lf a ta s e & g lu k u r o n id a s e u /
re g e n e r a s i m jd s e n y a w a
in d u k & d i r e a b s o r p s i

Phase I
B io tr a n s fo r m a tio n
(d e g r a d a t io n re a c tio n )

o x id a tio n
r e d u c tio n
h y d r o ly s is

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O X ID A T IO N


N o n - s p e c ific e n z y m e s
(p a r tic u la r ly c y to c h r o m e
P 4 5 0 e n z y m e s in th e
li v e r ) a r e a b l e t o a d d
p o la r fu n c tio n a l g r o u p s
to a w id e v a r ie ty o f
d r u g s . O n c e th e p o la r
fu n c tio n a l g r o u p h a s
b e e n a d d e d , th e o v e r a ll
d r u g is m o r e p o l a r a n d
w a te r s o lu b le .

S ito k ro m P -4 5 0







B M 3 5 -4 5 kD
5 1 f a m i l y C Y P ( h o m o l o g i > 4 0 %)
1 0 s u b fa m ily C Y P (h o m o lo g i >
5 5 %)
E x. C Y P 3 A 4
S p e s ifis ita s re n d a h , s is i k e r ja
b e rb e d a
C Y P y a n g b e rb e d a p a d a o b a t
y a n g s a m a b e k e r ja p a d a s is i
yang sam a
P d m e m b r a n R E h a ti, u s u s ,
o ta k , p a r u - p a r u , g in ja l

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C y to c h ro m e
P 450

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( 1 ) T h e n o r m a l s t a t e o f a P 4 5 0 w it h th e
ir o n in it s fe r r i c
[ F e 3 +] s t a t e .
( 2 ) T h e s u b s t r a t e b in d s to th e e n z y m e .
( 3 ) T h e e n z y m e is r e d u c e d to th e fe r r o u s
[ F e 2 +] s t a t e b y t h e a d d i t i o n o f a n e l e c t r o n
fr o m N A D P H c y t o c h r o m e P 4 5 0
re d u c ta s e . T h e b o u n d s u b s tra te
fa c ilit a t e s th is p r o c e s s .
(4 ,5 ) M o le c u la r o x y g e n b in d s a n d fo r m s a n
F e 2 +O O H c o m p l e x w i t h t h e a d d i t i o n o f a
p r o t o n a n d a s e c o n d d o n a t io n o f a n
e le c tr o n fr o m e ith e r N A D P H c y to c h r o m e
P 4 5 0 re d u c ta s e o r c y to c h ro m e b 5 . A
s e c o n d p r o t o n c l e a v e s t h e F e 2 +O O H
c o m p le x to fo r m w a t e r.
( 6 ) A n u n s t a b l e [ F e O ]3 + c o m p l e x d o n a t e s i t s
o x y g e n to th e s u b s t r a t e
( 7) T h e o x i d i s e d s u b s t r a t e i s r e l e a s e d a n d
th e e n z y m e r e t u r n s to it s in i t i a l s t a t e ( 1 ) .

S ito k ro m P -4 5 0
M e k a n is m e re a k s i o k s id a s i
s u b s tr a t o le h s ito k r o m P - 4 5 0
te r o k s id a s i (A ) :
N A D P H + A + H +
A H 2 +N A D P +
 A H 2 + O 2

O 2 a k tif + H 2 O
 O 2 a k tif + O 2 + R H

R O H + A
 R H + O 2 + N A D P H + H +
R O H +
H 2O + N A D P +


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O x id a t iv e
M e t a b o lis m


T h e la r g e s t c l a s s o f P h a s e I
m e t a b o l i c p r o c e s s e s in v o l v e s
o x id a t io n r e a c t io n s
C o m m o n o x id a t iv e p r o c e s s e s
in c l u d e :
T h e a d d it io n o f o x y g e n to
v a r io u s fu n c t io n a l g r o u p s
C h a n g in g th e h y b r id iz a t io n
o f g r o u p s fr o m s p 3 to s p 2 o r
fr o m s p 2 to s p b y re m o v a l o f
h y d ro g e n

10

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C o m m o n o x id a tiv e m e ta b o lis m s
in c l u d e :
A r o m a tic h y d r o x y a tio n s
A lip h a tic h y d r o x y la tio n s
E p o x id a tio n o f a lk e n e s
O x id a tio n o f a lc o h o ls to
a ld e h y d e s
O x id a tio n o f a ld e h y d e s to
c a r b o x y lic a c id s
O x id a tio n o f s u lfid e to
s u lfo x id e s to s u lfo n e s
O x i d a t i o n o f im i n e s t o im i n e
o x id e s
D e a lk y la tio n o n h e te r o a to m s

O X ID A T IO N

11

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R e d u c t iv e
M e t a b o lis m
R e d u c t i o n is a lo w e r in g
o f th e o x id a tio n s ta te o f
a g r o u p b y a d d in g
e le c tr o n s (u s u a lly a s a
h y d r id e ( H - ) io n ) .
T h u s a g r o u p th a t h a s
o n e d o u b le b o n d g e ts
re d u c e d to a s p e c ie s
c o n ta in in g o n ly a s in g le
b o n d (C = O C H -O H ).

12

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F u n c tio n a l g r o u p s th a t
m o s t ty p ic a lly u n d e r g o
m e ta b o lic re d u c t io n
in c l u d e :
K e to n e s
N itr o g r o u p s
A z o g ro u p s
L e s s c o m m o n ly ,
a ld e h y d e s a n d s u lfo x id e s
c a n b e re d u c e d .

13

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H y d ro ly s is
H y d r o ly s is is th e p r o c e s s
o f b r e a k in g b o n d s b y
th e a d d it io n o f w a t e r.
F u n c tio n a l g r o u p s th a t
a re m o s t o fte n
m e ta b o liz e d b y
h y d r o ly s is in c lu d e
e s t e r s ( a n d la c t o n e s )
a n d a m id e s ( a n d
la c t a m s ) .

14

11/0 9/2 0 12

y d r o ly s is o f e s te r s A L W A Y S
r e s u l t s in t w o p r o d u c t s a
c a r b o x y lic a c id a n d a n
a lc o h o l.
H y d r o ly s is o f a m id e s A L W A Y S
r e s u l t s in t w o p r o d u c t s a
c a r b o x y lic a c id a n d a n a m in e .
H y d r o ly s is o f c y c lic e s te r s a n d
a m id e s (la c to n e s a n d
la c t a m s ) r e s u l t s in r i n g
o p e n in g , g iv in g a c o m p o u n d
h a v in g a c a r b o x y lic a c id a t
o n e e n d o f th e c h a in a n d a n
a lc o h o l o r a m in e a t th e o t h e r.

M e c ha n i s m hy d r ol y s i s
T h e m e c h a n is m o f a
h y d r o ly s is re a c tio n re q u ir e s
a c a ta ly s t to c o o r d in a te w ith
a lo n e - p a i r o f e l e c t r o n s o n
th e c a r b o n y l o x y g e n .
D u r in g m e ta b o lic h y d r o ly s is
a n e n z y m e (a n e s te ra s e o r
a m id a s e ) fu n c tio n s a s th e
c a ta ly s t. T h e re s u lt o f th is
s t e p is t h a t t h e c a r b o n y l
c a rb o n b e c o m e s m o re
p o s itiv e ly - c h a r g e d th a n
n o r m a l.
W a t e r, w h i c h is a
n u c le o p h ile , a tta c k s th is
c a rb o n .

15

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P h a s e II
B io tr a n s fo r m a tio n
(c o n ju g a t io n r e a c t io n )

c o n ju g a tio n
a c e ty la tio n
m e th y la tio n

16

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In p h a s e II r e a c t io n s , s u b s t a n c e s a r e
c o m b in e d w ith e n d o g e n o u s
h y d r o p h i l i c c o m p o u n d s . T h e r e s u l t is
a s u b s ta n c e w ith s u ffic ie n t h y d r o p h ilic
c h a r a c te r to a llo w r a p id e x c r e tio n .

P ha s e II of b i ot r a n s f or m a t i on i s
c o n c e r n e d w i t h conjugation, t h a t i s u s i n g
g r o u p s fr o m c o fa c to r s to re a c t w ith
fu n c tio n a l g r o u p s p r e s e n t o r
in t r o d u c e d f r o m p h a s e I o n t h e
com pound.

T h e e n z y m e s in v o l v e d a r e a s e t
tr a n s f e r a s e s w h ic h p e r fo r m th e
tr a n s fe r o f th e c o fa c to r g r o u p to
s u b s tr a te . T h e re s u lta n t c o n ju g a
r e s u l t s in g r e a t l y i n c r e a s i n g t h e
e x c r e to r y p o te n tia l o f c o m p o u n d

of
th e
tio n
s.

P h a s e II
M e t a b o lite s
D u r in g p h a s e II m e ta b o lis m
p a re n t c o m p o u n d s a n d
p h a s e I m e ta b o lite s a r e
e ith e r d e to x ifie d o r
c o n v e r t e d in t o m o r e w a t e r s o lu b le e n titie s th a t c a n
th e n b e e x c r e te d .
C o m m o n c la s s e s in c lu d e :
G lu c u r o n id e c o n ju g a te s
S u lfa te c o n ju g a te s
G ly c in e a n d g lu ta m a te
c o n ju g a te s
G lu ta th io n e c o n ju g a te s
A c e ty la tio n
M e th y la tio n

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G lu c u ro n id e
C o n ju g a te s
A m o n g th e m o s t c o m m o n
p h a s e II m e ta b o lit e s
B o d y h a s la r g e s u p p ly o f
g lu c u r o n ic a c id , w h ic h is
m a d e fr o m D - g lu c o s e .
F u n c tio n a l g r o u p s
s u s c e p tib le to
g l u c u r o n i d a t i o n in c l u d e :
a lc o h o ls a n d p h e n o ls ,
c a r b o x y lic a c id s , a m in e s ,
th io ls

S u lfa te C o n ju g a te s
S u lfa te c o n ju g a t e s a r e fo r m e d
m a in ly fr o m p h e n o ls , a lth o u g h
th e y c a n a ls o b e fo r m e d fr o m
a lc o h o ls a n d a r o m a tic
a m in e s .
T h e r e is le s s a v a i l a b l e s u l f a t e
in t h e b o d y t h a n t h e r e is
g lu c u r o n ic a c id .
T h e c o e n z y m e 3 p h o s p h o a d e n o s i n e - 5 p h o s p h o s u l f a t e ( P A P S ) is
r e s p o n s ib le fo r tr a n s fe r r in g a
s u lfa te to a s u ita b le s u b s tr a te
in t h e p r e s e n c e o f t h e e n z y m e
s u lfo tr a n s fe r a s e

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G l yc i n e a n d G l u t a m i n e
C o n ju g a te s
G ly c in e a n d g lu ta m in e
fo r m c o n ju g a te s w ith
c a r b o x y lic a c id s .
T h e p ro d u c ts a re
c a r b o x y a m id e s , a n d a r e
m o r e w a te r - s o lu b le th a n
th e c a r b o x y lic a c id s .

G lu t a t h io n e
C o n ju g a te s
G l u t a t h i o n e ( G S H ) c o n j u g a t i o n is a
m e a n s b y w h ic h th e b o d y c a n d e t o x if y
r e a c t iv e e le c t r o p h ilic s p e c ie s .
 G lu t a t h io n e p o s s e s s e s a n u c le o p h ilic
th io l ( S H ) g r o u p th a t c a n r e a c t w it h
e le c tr o p h ile s b e fo r e th e y re a c t w ith
o t h e r n u c le o p h ile s s u c h a s th o s e th a t
b e lo n g to c r it ic a l c o m p o n e n t s ,
in c l u d i n g p r o t e i n s a n d D N A .
 M o s t o fte n , th e g lu ta th io n e c o n ju g a te s
a r e d e g r a d e d e n z y m a t ic a lly b y
c le a v in g th e g lu t a m ic a c id a n d g ly c in e
m o it ie s a n d th e n th e a m in o g r o u p o f
th e c y s t e i n e is a c e t y l a t e d .
G lu ta th io n e re a c ts w ith e le c tr o p h ile s
b y tw o m a in m e c h a n is m s :
N u c le o p h ilic s u b s t it u t io n
N u c le o p h ilic a d d it io n to a n e le c t r o n d e fic ie n t d o u b le b o n d

19

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A c e t yl a t i o n
P r im a r y a m in e s u n d e r g o

a c e ty la tio n
o f th e a m in o g r o u p to g iv e
a c e t a m id e s .
Un l i k e t h e o t h e r p h a s e I I m e t a b o l i c
p a t h w a y s a c e t y la t io n d o e s n o t
n e c e s s a r i l y le a d to m o r e w a t e r s o lu b le m e ta b o lite s .
A c e t y la t io n s e r v e s a s a m e a n s to
te r m in a t e th e a c t iv it y o r d e t o x if y
p r im a r y a m in e s .
P r im a r y a m in e s a r e o f t e n fo r m e d fr o m
p h a s e I re d u c tio n o f a r o m a tic n itr o
g ro u p s .
A c e t y l - C o A , in t h e p r e s e n c e o f N a c e ty ltr a n s fe r a s e s a d d s a n a c e ty l
g r o u p o n t o th e a m in e .
A c e ty la tio n c a n o c c u r o n th e p r im a r y
a m in o g r o u p o f a lip h a tic a n d
a r o m a t ic a m in e s , s u lf o n a m id e s ,
h y d r a z in e s , a n d h y d r a z id e s

M e t h yl a t i o n
M e t h y l a t i o n is a r e l a t i v e l y
m in o r p h a s e II m e t a b o lic
p a th w a y.
A m o n g th e g r o u p s th a t
u n d e r g o th is re a c tio n a r e
p h e n o ls , c a t e c h o ls (o r th o d ih y d r o x y a r o m a tic
c o m p o u n d s ) , a m in e s , a n d
th io ls .
M e th y la tio n d o e s n o t
in c r e a s e w a t e r s o l u b i l i t y ,
b u t it d o e s u s u a l l y r e n d e r
th e m e ta b o lite b io lo g ic a lly
in a c t i v e .

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22