CS_K18 (Drug Metabolism - Biotransformation)

8/17/2019 CS_K18 (Drug Metabolism - Biotransformation)

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DRUG

METABOLISM(BIOTRANSFORMA

TION)Aznan Lelo, Yunita Sari Pane

De! Far"a#olo$i %anTeraeuti#,

Fa#ulta& 'e%o#teran

Unier&ita& Su"atera

Fe*ruari +- 'B' .S/' -0 F' USU


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OBAT .oru& alienu" ter1a%a

(2eno*ioti3&)

4aru& %i#eluar

#an

Den$an 3ara aa 5 *a$ai"ana

Meta*oli&"e (*iotran&7or"a


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Now,we are talking about

…

Dru$ "eta*oli&"(Dru$ *iotran&7or"ation)


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Drug

Metabolism

• Drugs are most often eliminated by biotransformation&/or excretion in the urine or bile.

• The liver is the major site for drug metabolism.

• Some drugs require metabolic activation.


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Reactions of Drug Metabolism

• The kidney cannot efficiently eliminate liohilicdrugs because they are readily reabsorbed in thedistal tubule.

• !iid soluble drugs must first be metaboli"ed inthe liver using one or both of t#o generalreactions$


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Drug Metabolism (cont’d)

• T#o %hases$ and

' %hase $ conversion to

liohilic comounds ' %hase $ conjugation

• %hase involves the

cytochrome %()*+

system

• ,ltimate effect is to

facilitate elimination

Drug

%hase

%hase

-xidation

eductionydrolysis

0ctivation/nactivation

1onjugation %roducts

2lucuronidation


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Phase I reactions

• 1ytochrome %)*+ system

• !ocated #ithin the endolasmic

reticulum of heatocytes• Through electron transort chain3 a drug

bound to the 14%)*+ system

undergoes oxidation or reduction• 5n"yme induction

• Drug interactions


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Phase I reactions types

• ydrolysis

• -xidation

• eduction• Demethylation

• 6ethylation

• 0lcohol dehydrogenase metabolism


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Oxidasi (oxidation)

( meruakan reaksi yang aling utama terutama

yang menggunakan mixed(function oxidases(eactions that exose or introduce a functional

grou( ensim yang aling utama3 suatu haem rotein 7

cytochrome %)*+

8anyak isoensim 14%

berbeda kemamuan metabolisme ada individu

atau etnik / ras


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CP!"# $omenclature

CYP2D6

%amily

&ub'%amily Indiidual ene


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Obat-obat yang merupakan substrat bagiensim P45

P450 obat

Cyp 1A1 Teofilin

Cyp 1A2 Kafein, parasetamol, teofilin,

Cyp 2Cg Ibuprofen, asam mefenamat, fenitointolbutamid, warfarin

Cyp 1! Klo"apin, #odein, metoprolol, TCA

Cyp 2$1 Al#o%ol, enfluran, %alotan

Cyp & A 4'5 (i#losporin, eritromisin, ligno#ain,nefedipin, terfenadin


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P1a&e II rea3tion&

• Polar $rou i& 3on8u$ate% to t1e %ru$

• Re&ult& in in3rea&e% olarit9 o7 t1e%ru$

• T9e& o7 rea3tion& ' Gl93ine 3on8u$ation

' Glu3uroni%e 3on8u$ation

' Sul7ate 3on8u$ation

P1a&e II: 3on8u$ation (&9nt1eti3rea3tion)

.oalent lin#a$e *et;een t1e2eno*ioti3 or one o7 it&

"eta*olite& ;it1 a ;ater/&olu*le,en%o$enou& 3o"oun%, e!$!,$lutat1ione!


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P1a&e II rea3tion : &9nt1eti3 rea3t < 3on8u$ation 3on8u$ate

Bia&an9a %en$an : " $lu3uron9l

" &ul1ate" "et19l" a3et9l

" $l939l" $lutat1ione

En&i" : tran&7era&e


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A#i*at "eta*oli&"e o*at

Dala" ro&e& "eta*oli&"e o*at, ter8eru*a1an ter1a%a o*at, *erua=

-!Pen$uran$an lii% &olu*ilit9+! eru*a1an *iolo$i3al a3tiit9


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A%!-! Pen$uran$an lii% &olu*ilit9

tu8uann9a a%ala1 untu# "e"* le*i1 ;ater/&olu*le &e1in$$a%i#eluar#an ia urin!

" 'a%an$#ala : lii% &olu*le lii% i tai 8u$a ;ater in&olu*le "en %ala" urine

an8ur#an a&ien *an9


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A% +! Peru*a1an *iolo$i3al a3tiit

4a&il a#1ir "eta*oli&"e o*a a%ala1 *era#1irn9a e7e# o* Na"un a%a &ean8an$ ro

*iotran& 7or"a&i ini a%a *e* 9an$ ter8a%i!

a! o*at 9an$ a3ti7 ina#ti7*! o*at 9an$ a#ti7 a#ti73! o*at 9an$ a3ti7 to#&i# %! o*at 9an$ ina#ti7 a#ti7 (ro%r


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a!'oner&i o*at 9an$ a#ti7ina#ti7

"i&: a%renalin////////

"et19la%renalin

*! 'oner&i o*at 9an$ a3ti7

*a1an a#ti7 lain/lain "i&al:

) obat a#tif ) *etabolit a#tif

+ amitriptilin + nortriptilin

+ dia"epam + oa"epam

+ #odein + morfin

+ #%oro#in + %idroi#%loro#in

+ spironola#ton + #anrenon


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3! 'oner&i o*at 9an$ ina#ti7 a#ti7 (

nactive(substance 0ctive metabolite 1omment

1holecalciferol 9(alfa hidroxycholecalciferol

1ylohoshamide )(keto(cyclohoshamide

%erindroril %erindroilat !ess risk of first(dose hyotension

!evodoa Doamine !evodoa3 crossthe 8883

Terfenadine :exofenadina Tachycardia bilametabolisme dihambat


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%! O*at a#ti7 to#&i#/ ara&eta"ol 1eato#&i

/ i&oniazi% 1eatoto

/ &i#lo7o&7a"i% terato$eni


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O2i%a&i a%a 1a&e I a%a *e*eraao*at

"en$1a&il#an eo2i%e, *a1an 9an$a"atrea#ti7, 9an$ %aat *eri#atan &e3ara

#oalen%en$an *a$ian &el to#&i#!Mi&:ara&eta"ol,1alot1ane!Glutat1ione *eri#atan %en$aneo2i%e

menginaktifkan eo2i%e$lutat1ione

entin$ untu# en3e$a1an 5


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P>? an% *iolo$i3al ariationBan9a# 1al 9an$ "e"en$aru1i e2r

re$ula&i en&i" P>?

- Geneti# - Lin$#un$an

- Ma#anan $rae7ruit 8ui3e "en$1a "eta*oli&"e ter7ena% *ru&&el &rout& @ a&a

"en$in%u#&i enzi" P>/ O*at//// Dru$ /Intera3tion


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E+!, Enz9"e in1i*ition=

It i& t1e %e3rea&e o7 t1e rate o7"eta*oli&" o7

a %ru$ *9 anot1er one!T1i& ;ill lea% to t1ein3rea&e o7 t1e 3on3entration o7 t1e tar$et

%ru$ an% lea%in$ to t1e in3rea&e o7 it& to2i3it9 !In1i*ition o7 t1e enz9"e "a9 *e %ue to t1e 3o"on it& *in%in$ &ite& , &o t1e on&et o7 a3tion i& &1o"a9 *e ;it1in +>1!

N!B= 1en an enz9"e in%u3er(e!$!3ar*a"azeine) i& a%"ini&tere% ;it1 anin1i*itor (eraa"il) T1e eCe3t o7 t

in1i*itor ;ill *

re%o"inant


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E2!,Er9t1ro"93in in1i*it "eta*oli&" o7 astemazole

In3rea&e t1e &eru" 3on3!o7 t1e anti1i&ta"ini3 lea%in3rea&in$ t1e li7e t1reate

3ar%ioto2i3it9

E!, O"erazole In1i*it& o2i%atie

"eta*oli&"o7 %iazea"


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Fir&t/a&& "eta*oli&":

Oral a%"ini&tration in3rea&e& t1e31an3e 7or lier

an% GIT "eta*oli&" o7 %ru$& lea%in$

to t1e lo&& o7 aart o7 t1e %ru$ %o&e %e3rea&in$ it&a3tion! T1i& i&

"ore 3lear ;1en &u31 %ru$ i& an

enz9"e in%u3eror in1i*itor!

E!, Ri7a"in lo;er& &eru" 3on! o7 eraa

in3rea&e it& r&t a&& ! Al&o, Ri7a"in1eati3 "eta*oli&" o7 eraa"il


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ENSIM LAIN! (&elain .9) untu# o2

- al3o1ol %e19%ro$ena&e- 2ant1ine o2i%a&e- "onoa"ine o2i%a&e


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Mi3ro&o"al enz9"e&:- In%u3tion- In1i*ition

o*atP1a&e I

Meta*olit IP1a&e II

Meta*olit II

Ina#ti7"a#ti7 " ina#ti7 " to#&i# (ara&eta"ol)

A#i*at / in%u#&i/ in1i*i&i 6


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#n$yme %n&u'tion

(brp obat--- mengin&uksi )merangsang

P45 &g *memper'epat sintesa,atau

*meng+ambat perombakan

***

ensim bertamba+**

perombakan obat makin 'epat** eek berkurang!

OBAT MANA6!Obat pengin&uksi

2!Obat lain yg &iberi bersama yang ensimnya

Enz9"e In1i*itor #e*ali#an %ariEnz9"e In%u3tion


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#./0P1#In%u3er& : In1i*itor:

/P1en9toin /O"erazole/.ar*a"azeine /Di&ulra"

/Bar*iturate /Er9tr1ro"93in

/Ri7a"in /aroi3 a3i%

/Ritonair /I&oniazi%/.1roni3 et1anol to2i3it9 /.i"eti%ine

/Gri&eo7uln /.iroo2a3in

/A3ute et1anol

to2i3it9


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Enz9"e In%u3tion 5 in1i*ition: Pe"*erian o*at *er/ulan$+ %aat"en9e*a*#an 1al %i*a;a1 ini:• #nsim perombaknya meningkat

akti3tasnya

enz9"e/in%u3er

• #nsim perombaknya &itekanakti3tasnya

enz9"e/in1i*itor

• Ensim perombak obat lain uga

&ipengaru+i!


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Fir&t/a&& (re&9&te"i3 "eta*oli

*ia&an9a "en9u&a1#an ole1 #aa#i*atn9a:

/ %i*utu1#an %o&i& 9an$ *e&ar *ila!o oral *ioaaila*ilit9 8ele#!

/ %i*eri#an %en$an 3ara lain,"i&:


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Fa#tor 7a#tor 9an$ "e"en$ar"eta*oli&"e o*at:

-!Internal : / &e&ie& / $eneti# / &e2 / u"ur

/ 1or"on/ #e1a"ilan

/ en9a#it

+! E#&ternal :/ %iet / lin$#un$an:

- Ma#anan- Al#o1ol

- Ro#o# 5ni#otin

CS_K18 (Drug Metabolism - Biotransformation)

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Transcript of CS_K18 (Drug Metabolism - Biotransformation)