Clinical Pharmacokinetics (biotransformation)

8/18/2019 Clinical Pharmacokinetics (biotransformation)

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Dr. Kamal PatelFirst Year Resident

16/01/2016

Clinical Pharmacokinetics II


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•

Introduction

• Sites of metabolism

• First pass metabolism

• Pathways of metabolism

• Drug transport

• Enzymes involved in metabolism

• Enzyme induction and inhibition

• Factors aecting metabolism

Biotransformation


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• Chemical alteration of dr! in "od# mediated "# en$#me

• %n$#me catal#sed "iochemical transformation of &eno"io

li(in! or!anism

• Co)in! mechanism to &eno"iotics

• *eno"iotics + all chemical s"stances that are forei!n to

enter thro!h in!estion, inhalation or dermal e&)osre

%.!. + dr!s, indstrial chemicals, )olltants, )lant andto&ins

I-RDCI-


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• Biotransformation )la#s role in

ermination of dr! eect

Protection from to&ic meta"olite

Bio acti(ation

Carcino!enesis

o&icit#

Con(ersion of non3)olar 4 )olar and li)id sol"le 4 'a


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1. Pharmacolo!ical inacti(ation occrs in most cases %.!. Pheno"ar"itone 7#dro)heno"ar"itone

8acti(e dr!9 8inacti(e meta"olite9

2. Bio acti(ation or to&icolo!ical acti(ation in case of )ro)rocarcino!ens

%.!. :3Do)a8inacti(e9 Do)amine8acti(e9

. ;cti(e meta"olite formation from e


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• :i(er >a?or site

• Kidne#

• Intestine

•

:n!s

• @kin

• ;drenal corte&

• Placenta

@ites of meta"olism


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• >eta"olism of dr! "efore reachin! s#stemic circlation

• ;ects dr!s taken "# oral and inhalation rotes

• Decreases "ioa(aila"ilit# Diminished thera)etic

• Insi!niAcant if meta"olism )rodces acti(e meta"olites e

)ro)ranolol

• 7i!hl# si!niAcant in li(er im)airment

• Can "e "#)assed "# chan!e of rote of administration

%.!. lidocaine "# i.(. rote, isosor"ide dinitrate "# s"

rote

First )ass meta"olism


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• :i(er >or)hine, Pethidine, *#locaine, Imi)ramine, ;mit

Pro)ranolol, Isosor"ide dinitrate, l#cer#l trinitrate

• Intestinal >cosa :3do)a, 3meth#ldo)a, #ramine, es

Pro!esterone, Chlor)roma$ine• Bronchial >cosa -icotine, Iso)renaline

First )ass meta"olism occrrin! in


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• De)endin! reaction t#)e

Phase I reactions &idation, Redction, 7#drol#sis

Phase II reactions Con?!ation reactions

• De)endin! on en$#me in(ol(ed

>icrosomal -on3microsomal

Path'a#s of meta"olism


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• @#nthetic reactions

• Con?!ation reactio

• %ndo!enos radical

to the dr!

•

Con?!ation

Phase II reaction

• De!radati(e/-on3s#nthetic

reactions

• Fnctionali$ation reaction

• Fnctional !ro) !enerated or

e&)osed

• &idation, Redction,

7#drol#sis

Phase I reactions


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• >icrosomal, >itocho

C#to)lasmic en$#m

• ransferases

• >eta"olite is mostl#

e&ce)t

>or)hine !lcro

@lfate con?!ate

Phase II reaction

• >ainl# >icrosomal en$#mes

• C#tochrome P5=0, Fla(in

mono3o!enase, %7

• >eta"olite ma# "e acti(e or

inacti(e

Phase I reaction


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A!"idation1. >icrosomal o&idations

;romatic h#drolation R R

Phen#toin

Garfarin

Pheno"ar"itone Pro)ranolol

Phase I reactions


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• ;li)hatic h#drolation 8side chain h#drolation9

Pento"ar"itone Di!ito&in

C#clos)orine

• Dealk#lation

>e)ho"ar"itone Pheno"ar"itone 8-3dealk#lation9

;mitri)t#line -ortri)t#line 8-3dealk#lation9 Codeine >or)hine 83dealk#lation9

63>eth#lthio)rine >erca)to)rine 8@3dealk#lation

R3C723C7 R3C7

C7


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• -3 &idation

Chlor)heniramine Hinidine

• @3 &idation

Chlor)roma$ine

Cimetidine

• Deamination

;m)hetamine Phen#lacetone deri(ati(e


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• Deslfari$ation

Parathion to Parao&on

• %)o&ide formation

Car"ama$e)ine


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2. -on3microsomal &idations

>itochondrial &idations Catecholamine o&idation "# monoamine o&idase

&idati(e deamination

7istamine

*anthine


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C#to)lasmic &idation 8deh#dro!enation9

;lcohol ;cetaldeh#de ;cetic ;cid

P#rido&ine

Decar"olation

:e(odo)a


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# $eductions1. >icrosomal redctions

-itro redctionR3-2 R3-72J Chloram)henicol to ar#l3amine meta"olite

;$o redction R3--3R1 R-72 L R1-72 J

Prontosil 8)rodr!9 to @lfanilamide and redctio@lfasala$ine

Keto redction R38C93R1 R38C7793R1J Cortisone, >ethadone, -alo&one


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2. -on3microsomal redction

Chloral h#drate richloroethanol


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% &ydrolysis

>ostl# non3microsomal e&ce)t Pethidine, :idocaine Breakdo'n of molecle 'ith hel) of 'ater molecle

%n$#mes esterase, amidase, )e)tidase, e)o&ide h#)hos)hatase, )rotease

@ites li(er, intestine, )lasma and other tisses

%.!. Procaine, ;s)irin, @ccin#lcholine, ;tro)ine,

Procainamide, Car"ama$e)ine, M3lactam rin! of )eni


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;. lcronide con?!ation

nl# microsomal con?!ation

Dr! or their meta"olite 'ith )henolic, car"olic, ammerca)to !ro)

Increases moleclar 'ei!ht

%n$#me DP3!lcron#l transferase Con?!ate ridine di)hos)hate !lcronic acid

Phase II reactions


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%.!. as)irin, chloram)henicol, dia$e)am, lora$e)am,)aracetamol

%ndo!enos s"stances "ilir"in, steroidal hormone

Im)ortant role in enterohe)atic circlation of dr!s an)rolon!in! dr! action

%.!. )henol)hthalein, oral contrace)ti(es


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B. -3;cet#l con?!ation

%n$#me -3 acet#l transferase

Co3factor acet#l coen$#me ;

@ite c#to)lasm of (arios or!ans

@"strate aromatic amines and com)ond 'ith h#dreside

%n$#me controlled "# mlti)le !enes !enetic )ol#m

%.!. isonia$id, P;@, da)sone, sl)honamide, h#drala R3-72 R3-73CC7


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C. @lfate con?!ation

%n$#me Famil# of slfotransferase @:J

Co3factor N)hos)hoadenosine3=3)hos)hoslfate

@ite c#to)lasm of (arios or!ans

@"strate )henolic, alcoholic and aromatic amine d

%.!. chloram)henicol, h#drol3comarins, meth#ldadrenal and se& steroids


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D. ;mino acid con?!ation

>inor )ath'a#

Con?!ated 'ith !l#cine or !ltamine

%n$#me ;c#l3coen$#me ; !l#cine transferase

@ite mitochondria

For dr!s 'ith car"olic acid !ro) %.!. salic#lates, "en$oic acid, nicotinic acid, deoc


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%. >eth#l con?!ation

>inor )ath'a#

%n$#me transmeth#lase/ meth#l transferase

Cofactor @ adenosine methionine

@"strate amines and )henols

%.!. catecholamines, histamine, meth#ldo)a, ca)to


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F. ltathione con?!ation 8c#tosol9

>inor )ath'a#

%n$#me !ltathione s3transferase

@"strate e)o&ides, -2 !ro) containin! dr!s an

h#drolamines

%.!. ethacr#nic acid, slfo"romo)hthalein Im)ortant in inacti(ation of hi!hl# reacti(e


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. Ri"oncleoside and Ri"oncleotide s#nthesis

>inor )ath'a#

Prine and )#rimidine antimeta"olites form their actimeta"olite "# formin! ri"oncleosides and ri"oncle


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• rans)ort into enteroc#te• ;cti(e e&cretion into intestinal l

ral "ioa(aila"ilit#

• rans)ort into he)atoc#te• %&cretion in "ile7e)atic meta"olism

• rans)ort into )ro&imal t"lar • %&cretion into t"lar lmen

Renal clearance

;cti(e dr! trans)ort


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• ral "ioa(aila"ilit#

>DR31 or P3!l#co)rotein eO& trans)orter

%.!. di!o&in, 7I31 )rotease inhi"itors

• Dr! meta"olism from )ortal circlation

;P 8or!anic anion trans)ortin! )e)tide9 and C 8orcation trans)orter9

Rele(ant for 7> Co3; redctase inhi"itors 8statins9

%.!. )ra(astatin meta"olism ;P1B1 trans)orts ihe)atoc#te

)re(ents rha"dom#ol#sis )re(ents )take "# mscle


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• Renal clearance

r!anic anion trans)orter renal secretion of anionic d

%.!. M lactam anti"iotics, -@;IDs, anti(iral ncleoside


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•

'icrosomal enzymes :ocation smooth endo)lasmic reticlm

r!ans li(er, kidne#, intestinal mcosa, ln!s

-ons)eciAc in action meta"olism of onl# li)id sol"le

Can "e indced or inhi"ited

Catal#se most of )hase I reactions and )hase II !lccon?!ation

%.!. C#tochrome P5=0, >ono o!enases, , %)o&h#drolases

%n$#mes


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• %n$#me s)erfamil# 'ith heme molecle "ond to )ol#)

chain

• Re


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• CYP5=0 redced form 'ith C forms )ink com)ond 'i

a"sor)tion )eak at 5=0nm

• CYPs in(ol(ed in *eno"iotic meta"olism CYP1, CYP2, CY

• CYP; Q CYP2D Q CYP2C Q CYP2%

• %&hi"it !enetic )ol#mor)hism


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%(P)A* + %(P)A, %(P-D.

Dr!s -earl# =0 2= 0

@"strates

C#clos)orine,%r#throm#cin, ;tor(astatin,Ritona(ir, >ida$olam,@ildenaAl

C;s, @@RIs, -eroCodeine, Flecainide"lockers

Indcers

Bar"itrates, Phen#toin,Rifam)icin,

Car"ama$e)ine, @t.SohnNs'ort

nkno'n

Inhi"itors>acrolides, ;ntifn!al,Ritona(ir, era)amil,Diltia$em

Hinidine, Flo&etin;miodarone, 7alo)

CYP;5QCYP;= enetic )ol#mor)h


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%(P-%/ + %(P-%0 %(P-%Dr!s 1= 1E 8109 12 1=

@"stratesPhen#toin, Garfarin,Car"ama$e)ine, :osartan,I")rofen

Clomi)ramine,me)ra$ole, CloPro)ranolol, Dia

Indcers Bar"itrates, Rifam)icin Rifam)in, PrednCar"ama$e)ine

Inhi"itors Flcona$ole, ;miodaroneme)ra$ole, FlRitona(ir


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%(P1A1 + %(P1A- %(P-E

@"strates

heo)h#lline, Caeine,

Paracetamol,Car"ama$e)ine

;lcohol, 7alothan

%nTrane, Parace

Indcers

Bar"itrates, Rifam)icin,Car"ama$e)ine, Ci!arettesmoke, Pol#c#clich#drocar"ons, Charcoal

"roiled meat

Chronic alcoholisIsonia$id

Inhi"itors Hinolones, Fl(o&amine DislAram

;cti(ation of )rocarcino!en


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• Catal#se o&idation at -, P or @ atom

• 6 families F> im) for meta"olism

• Distinct from c#tochrome P5=0

• @"strates Cimetidine, Ranitidine, Clo$a)ine, Ito)ride

• enetic deAcienc# Fish odor s#ndrome >; 4 >;J

• Ito)ride (s Cisa)ride im) for ne' dr! de(elo)ment

Fla(in >onoo!enase


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• %)o&ide h#drolase

2 t#)es3 sol"le and microsomal

Inacti(ates hi!hl# reacti(e electro)hile )rodced "# CY

%.!. car"ama$e)ine

Inhi"ition acti(e meta"olite side eects


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• Present in c#to)lasm, mitochondria, )lasma

• >ono3amine o&idase, %sterase, ;midase, ransferases, C

• Catal#ses )hase II reactions mostl#, some o&idation, red

h#drol#sis

• sall# non indci"le "t can "e inhi"ited

• enetic (ariation

Psedocholinesterase, ;cet#l transferase

-on microsomal en$#mes


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• 7oman elimination

• ;tracrim and Cis3atracrim

• >eta"olism "# moleclar rearran!ement 'ithot en$#me

in(ol(ement

-on en$#matic "iotransformation


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*eno"iotics "indto nclear

rece)tors P*R,C;R, ;hRJ

*eno"ioticnclear rece)tor

acti(ation

Cotrans

n

Com)to )ro

Increasedtranscri)tion

Increasede&)ression of

en$#mesCYP5=0, sJ

%n$#me indction


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• Conse to&icit#

olerance 8atoindction9 e.!. Car"ama$e)ine, Rifam)

Preci)itate acte intermittent )or)h#ria

• hera)etic ses

Con!enital non haemol#tic anaemia 3 Pheno"ar"itone

Cshin! s#ndrome Phen#toin Chronic )oisonin!


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•

Com)etiti(e inhi"ition e.!. ketocona$ole• Irre(ersi"le inhi"ition e.!. seco"ar"ital

• Fast )rocess com)ared to indction

• V )lasma concentration of dr! 4 Dr! to&icities

• hera)etic se Ritona(ir in s"3thera)etic doses 'ith :o)ina(ir

• Dr! trans)orters indced or inhi"ited

>acrolides inhi"it >DR1 4 increased serm Di!o&in le

%n$#me inhi"ition


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• ;!e and ender Children lo' acti(it# of DP 4 ra# "a"# s#ndrom

8chloram)henicol9, neonatal ?andice

%lderl# 3 U he)atic "lood To' and en$#me acti(it# 4 Umeta"olism 8)ro)ranolol, )ethidine9

Factors aectin! meta"olism


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• Race and ethnicit# Chinese hi!h alcohol deh#dro!enase and lo' aldeh#

deh#dro!enase

Cacasians E has fnctionall# inacti(e CYP2D6 8C"lockers, Codeine9

Garfarin 3 V sensiti(it# in ;sian3;merican, U sensiti(it;frican3american

• Diet and %n(ironment

;lter dr! meta"olism "# indction or inhi"ition of en$

ra)e frit ?ice inhi"it CYP;5


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• Diseases >ainl# li(er )atholo!ies and th#roid d#sfnction

• Dr!3Dr! interactions

De to en$#me indction or inhi"ition


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• enetic ;t#)ical )sedocholinesterase atosomal recessi(e t

-3acet#l transferase !enetic )ol#mor)hism

Codeine CYP2D6 )ol#mor)hism


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• Frank S, >ichael C, Ro"ert 7. Dr! >eta"olism. In+ Brn

editor. oodman W ilmanNs he Pharmacolo!ical Basis

hera)etics. 12th edition. -e' York+ >c ra' 7ill

P"licationX2011.).123155.

• ani!chi C, en!erich FP. Dr! >eta"olism. In+ olan D

Princi)les of Pharmacolo!# the )atho)h#siolo!ic "asis of

thera)#. rd edition. -e' Delhi+ Golters Kl'erX 2012. ).

• @harma 7:, @harma KK. Princi)les of Pharmacolo!#. 2nd

7#dera"ad+Paras >edical P"lisher, 7#dera"ad, 2011. ).

References

Documents

Clinical Pharmacokinetics (biotransformation)