Irsan Pharmacogenetics Meeting

8/18/2019 Irsan Pharmacogenetics Meeting

1/15

DISTRIBUTION AND PREVALENCEDISTRIBUTION AND PREVALENCE

OF CYP2C19 POLYMORPHISMOF CYP2C19 POLYMORPHISM

THAT UNDERLIE PMs PHENOTYPE THAT UNDERLIE PMs PHENOTYPE

IN INDONESIAN POPULATIONIN INDONESIAN POPULATION


2/15

Introducton !Introducton !

P"#r$#co%&n&tcs s stud' o( )n*#%& +&t,&&nP"#r$#co%&n&tcs s stud' o( )n*#%& +&t,&&n

nd-du#).s %&n&tcs #nd nd-du#).s #+)t' tond-du#).s %&n&tcs #nd nd-du#).s #+)t' to

r&s/ons& to dru%s0r&s/ons& to dru%s0

Ind-du#) -#r#ton n r&s/ons& to dru%s s #Ind-du#) -#r#ton n r&s/ons& to dru%s s #$#or /ro+)&$ n c)nc#) /r#ctc& #nd n dru%$#or /ro+)&$ n c)nc#) /r#ctc& #nd n dru%

d&-&)o/$&nt0d&-&)o/$&nt0

&n&tc -#r#nts d&t&r$n& nd-du#) dru%s&n&tc -#r#nts d&t&r$n& nd-du#) dru%s

r&s/ons&0r&s/ons&0 T"& $ost ,&))3c"#r#ct&r4&d %&n&s #5&ctn% dru% T"& $ost ,&))3c"#r#ct&r4&d %&n&s #5&ctn% dru%

r&s/ons& #r& t"& dru%3$&t#+o)s$ %&n&s6 suc" #sr&s/ons& #r& t"& dru%3$&t#+o)s$ %&n&s6 suc" #s

CYP2C19CYP2C19


3/15

&n&tc B#c*%round o( Dru% M&t#+o)s$&n&tc B#c*%round o( Dru% M&t#+o)s$

CYP2C19 s c'toc"ro$& P378 su+(#$)'CYP2C19 s c'toc"ro$& P378 su+(#$)'

r&s/ons+)& (or t"& $&t#+o)s$ o( dru%s suc"r&s/ons+)& (or t"& $&t#+o)s$ o( dru%s suc"

#s #ntcon-u)s#nt :S;3$&/"&n'ton6#s #ntcon-u)s#nt :S;3$&/"&n'ton6

o$&/r#4o)&6 c&rt#n +#r+tur#t&s6 d#4&/#$6o$&/r#4o)&6 c&rt#n +#r+tur#t&s6 d#4&/#$6

/ro/r#no)o)6 ct#)o/r#$6 /ro%u#n)


4/15

Drug Reference

Amitriptyline Melstrom et al , 1988

Barbiturates Adedoyin et al, 1994

Chlorproguanil right et al, 199!

Citalopram "indrup et al, 199#

Clomipramine $ielsen et al, 1994

Dia%epam Bertillson et al, 1989

&mipramine 'aefeli, et al, 199(Mephenytoin de Morias et al, 1994

)mepra%ole Anderson et al, 199*

+roguanil Andersson et al, 199(

+ropranolol ard et al, 1989

PHARMACEUTICAL SUBSTRATES OFPHARMACEUTICAL SUBSTRATES OF

CYP2C19CYP2C19


5/15

POLYGENIC DETERMINANTS OF DRUG EFFECTS

Drug Metabolism Genot!es

ime -hours.

0 5 10 15 20 25

D r u g C o n c e n t r a t i o n - / .

0

20

40

60

80

100

0t0t

0tm

mm


6/15

Fr&?u&nc' #nd Dstr+utonFr&?u&nc' #nd Dstr+uton

T"& $/#ct o( %&n&tc +#c*%round to dru% T"& $/#ct o( %&n&tc +#c*%round to dru%

/r&scr/tons !/r&scr/tons !

3 $&dcn&3 $&dcn& 3 soco3&cono$c3 soco3&cono$c

Fr&?u&nc' o( PMs "#s +&&n r&/ort&d!Fr&?u&nc' o( PMs "#s +&&n r&/ort&d!

@ 3 n C#uc#s#ns #nd A(rc#ns@ 3 n C#uc#s#ns #nd A(rc#ns@ 132 n As#ns@ 132 n As#ns

@ 1 n V#nu#tu /o/u)#ton :A*r#@ 1 n V#nu#tu /o/u)#ton :A*r# et alet al0;0;


7/15

(

1(

*(#(

4(

!(

2(3(

8(

9(

1((

hmM htM +M

Caucasian

African

5orea

China

6apan

+hilippines

7anuatu

INTERET"NIC #ARIATIONS OFINTERET"NIC #ARIATIONS OF

CYP$C%& GENOTYPECYP$C%& GENOTYPE


8/15

T,o /oss+)& "'/ot"&ss (or "%" (r&?u&nc' o( T,o /oss+)& "'/ot"&ss (or "%" (r&?u&nc' o(

PMs n V#nu#tu /o/u)#ton!PMs n V#nu#tu /o/u)#ton!

S&)&ct-& /r&ssur&0S&)&ct-& /r&ssur&0

&no+otc < $#)#r# &nd&$c n t"s /o/u)#ton&no+otc < $#)#r# &nd&$c n t"s /o/u)#ton

s"o, d&-#ton o( H#rd'3&n+&r% &?u)+ru$0 It.ss"o, d&-#ton o( H#rd'3&n+&r% &?u)+ru$0 It.sun)*&)' t"#t s&)&ct-& /r&ssur& /)#' $/ort#nt ro)&0un)*&)' t"#t s&)&ct-& /r&ssur& /)#' $/ort#nt ro)&0

&n&tc dr(t (ro$ Austron&s#n3s/*n% /o/u)#ton0&n&tc dr(t (ro$ Austron&s#n3s/*n% /o/u)#ton0

M%r#ton o( Austron&s#n3s/*n% /o/u)#ton (ro$M%r#ton o( Austron&s#n3s/*n% /o/u)#ton (ro$sout"3st As# to V#nu#tu s)#nds ,t" $n$#)sout"3st As# to V#nu#tu s)#nds ,t" $n$#)

nt&r#cton ,t" V#nu#tu s)#nd&rs0nt&r#cton ,t" V#nu#tu s)#nd&rs0


9/15

M&t"odsM&t"ods

CYP2C19 %&not'/n% "#s +&&n don& +' PCR3CYP2C19 %&not'/n% "#s +&&n don& +' PCR3

RFLP $&t"ods0RFLP $&t"ods0

T"& str#t&%' :s&& n&>t s)d&; T"& str#t&%' :s&& n&>t s)d&;

To d&t&ct CYP2C19 To d&t&ct CYP2C19$1$16 &>on 8 ,#s #$/)&d on 8 ,#s #$/)&d <

d%&st&d +'d%&st&d +' SmaI.SmaI. E>on 7 ,#s #$/)&d on 7 ,#s #$/)&d <

d%&st&d ,t"d%&st&d ,t" BamHIBamHI6 to d&t&ct CYP2C196 to d&t&ct CYP2C19$2$200


10/15

S T R A T E G Y S T R A T E G Y

#*1 bp

*1* bp

*31 bp

13! bp

C+*C19wt

C+*C19m1

C+*C19wt

C+*C19m2

)$ ! Intron 4 Intron 5

5’ 3’

)$ !

Intron 4 Intron 5

5’ 3’

1(9 bp *1* bp

#*1 bp

Sma &

1(9 bp

)$ 4

Intron 3 Intron 4

5’ 3’

)$ 4 Intron 3 Intron 4

5’ 3’

13! bp 92 bp

*31 bp

Bam' &

92 bp

wt/wt wt /m1 m1/m1

wt/wt wt /m2 m2/m2

Sma & Digestion

Bam' & Digestion


11/15

r&su)tr&su)t

M 1 2 3 4 5 6 7 8

M 1 2 3 4 5

:on !

1 ; e:on ! uncut

* < # ; 0t0t

4 ; m1m1! ; 0tm1

:on 41 ; e:on 4 uncut

*,#,2,3,8 ; 0tm*

4,! ; 0t0t

#*1 bp

*31 bp

13! bp

*1* bp


12/15


CYP$C%& GENOTYPECYP$C%& GENOTYPE

(

1(

*(

#(

4(

!(

2(

3(

8(

9(

1((

hmM htM +M

Caucasian

African

China

5orea

6apan

+hilippines

&ndonesia

7anuatu


13/15

0

10

20

30

40

50

60

70Melayu

6a0a=6epara

"unda

Daya>

Bugis

5a?ang


CYP$C%& GENOTYPE in in'onesian !o!ulationCYP$C%& GENOTYPE in in'onesian !o!ulation

hmM htM +M


14/15

CONCLUSIONCONCLUSION

Mut#ton ,"c" s "#//&n nMut#ton ,"c" s "#//&n n

Indon&s#n /o/u)#ton s Sout"3Indon&s#n /o/u)#ton s Sout"3

E#st As#n $ut#ton0E#st As#n $ut#ton0 Int&r&t"nc -#r#ton o( CYP2C19 nInt&r&t"nc -#r#ton o( CYP2C19 n

Indon&s#n /o/u)#ton n&&d (urt"&rIndon&s#n /o/u)#ton n&&d (urt"&r

&>/)or#ton0&>/)or#ton0


15/15

DRUG CYP$C%& PAT"(AY %∆ORAL CLEARANCE)

%**+,em)PM-.em

Carosiprodol N-demethylation 84% decline

Diazepam N-demethylation 56% decline

R-Hexobarbital 3α −hydroxilation !5% decline

"ansoprazole ρ - hydroxilation 85% decline

#-$ephenytoin 4 - hydroxilation !!% decline

R-$ephobarbital 4 - hydroxilation !8% decline estimate&

$oclobemide C- hydroxilation 63% decline

N-Desmethyldiazepam 3 - hydroxilation 55% decline'meprazole 5 - hydroxilation 86% decline

(& )antoprazole '-demethylation 84% decline

(& Citalopram N-demethylation 43% decline

Clomipramine N-demethylation 33% decline

*mipramine N-demethylation 4+% decline

)ro,anil cyclo,anil .ormation 4/% decline

)ropranolol side chain oxidation +5% decline

0lprazolam n1no2n 3% decline

Clozapine n1no2n /% declineDesmethylimipramine n1no2n /% decline

Diphenylhydantoin R-ρ - hydroxy 4% decline

loxamine n1no2n % decline

libenclamide n1no2n /% decline

"osartan n1no2n /% decline

$eprobamate n1no2n /% decline

Nicer,oline n1no2n /% decline

7riazolam n1no2n 6% decline

R-ar.arin 9 - hydroxilation :/% decline

Irsan Pharmacogenetics Meeting

Documents