the principle of pharmacokinetic

8/17/2019 The Principle of Pharmacokinetic

1/33

Novi Irwan FauziKK Farmakologi

Oktober 2015

Sekolah Tinggi FarmasiIndonesia

T! "#IN$I"%!S OF

"'&$OKIN!TI$

[email protected] @OppieFauzi


2/33


3/33

Movement of drugs across cellmembranes

Fulton, UCSF


4/33

Membranes• Types of Membranes:

• $ell 'embranes( This barrier is permeable to manydrug molecules but not to others, depending on theirlipid solubility. mall pores, ! angstroms, permit smallmolecules such as alcohol and water to pass through.

• )alls o* $a+illaries( "ores between the cells are

larger than most drug molecules, allowing them topass freely, without lipid solubility being a factor.

• ,lood-,rain ,arrier( This barrier provides aprotective environment for the brain. peed oftransport across this barrier is limited by the lipid

solubility of the psychoactive molecule.• "la.ental ,arrier( This barrier separates twodistinct human beings but is very permeable to lipidsoluble drugs.


5/33

Anatomy of the intestines


6/33

&natom/ o* the intestines


7/33

Absorption at brush border cells

Taken from Camitro Web Site

• !assive transcellular thought to be ma"or route• #on$charged compounds diffuse best


8/33

Me#anisme $mum Obat %intasMembran

• "assive Transport

"aracellular

Transcellular: &ifusi "asif %angsung

&ifusi "asif Terfasilitasi '()uaporin,#anal ion, dll*

• (ctive Transport

• +ndositosi dan +#sositosis


9/33

&rug &istribution

• &ependent upon its route of administration and target area,every drug has to be absorbed, by diusion, through avariety of bodily tissue.

• Tissue is composed of cells which are encompassed withinmembranes, consisting of - layers, layers of water/solublecomple0 lipid molecules 'phospholipid* and a layer of li)uid

lipid, sandwiched within these layers. uspended within thelayers are large proteins, with some, such as receptors,transversing all - layers.

• The permeability of a cell membrane, for a speci1c drug,depends on a ratio of its water to lipid solubility. )ithin thebod/ drugs ma/ eist as a miture o* two

inter.hangeable *orms either water ionized3.harged4 or li+id non3ionized4 soluble Theconcentration of two forms depends on characteristics ofthe drug molecule 'p2a, p3 at which 456 of the drug isionized* and the p3 of 7uid in which it is dissolved.

• In water soluble *orm drugs .annot +ass throughli+id membranes but to rea.h their target area the/


10/33

"rotein 8inding

Reversible and rapid

epends on !free dru"#, affinit$ for bindin" sites, !protein#


11/33

"rotein binding

• Many drugs bind to plasma proteins % (lbumin 'acidic drugs, eg warfarin,

9(&s*

% (lpha/; acid glycoprotein 'basic drugs,eg )uinine*

% %ipoproteins 'basic drugs*

%


12/33

"lasma "roteins that 8ind&rugs• albumin: binds many acidic drugs

and a few basic drugs

• 3globulin and an α;a.id

gl/.o+rotein have also been foundto bind certain basic drugs


13/33

Metabolism

!hase %&• 'ydroylation• Dealylation•

Sulfoide and #itroide formation• etc*

!hase + (Con"ugation)• lucuronide formation• Sulfation• lutathione Con"ugation• Cysteine Con"ugation• Acetylation•

etc*

'etabolism o..urs in liver gut wall lungs

kidne/s and other organs(


14/33

'etabolism

• Removes toic substances and drugs from the blood*• Cytochrome !,-.s are the ma"or drug metaboli/ing

en/ymes0 they are found in every organ in the body*• 1he body generally maes compounds more polar so

they are more readily ecreted in the idney*

%iver is the ma6or metabolizing organ in the bod/(


15/33

$/to.hrome "750 in #at and 'an(S+e.ies 8i9eren.es


16/33

"ro+ortion o* 8rugs'etabolized

b/ the 'a6or $:"s

$:" 1&2

$:" 28;

$:" 2$

$:"


17/33

8rug 3 8rug Intera.tions

Inhibition o* $:"

enz/mes

&ecreased degradationof comedicated drugs

ncreased drug plasma

concentrations

=is# of severe

adverse events

Indu.tion o* $:"

enz/mes

ncreased degradationof comedicated drugs

&ecreased drug plasma

concentrations

%oss of pharmacological

eect

=is# of severe

secondary eects

Riss associated with C2! en/yme inhibition or induction


18/33

Drug in

!ortal

3lood

8rug inIntesti

ne

4cretion

in

5eces

Metabolismin 6iver

Con"ugates

!hase$7

3ile

Drug in

3lood

4cretion

in

8rine

$on6ugates

in

Intestines

3eta$

glucuronidase

Absorption

Routes of 4cretion


19/33

www.wits.ac.za/fac/med/pharmacy/bio-elim.ppt

Renal 4cretion

Renal ecretionRenal ecretion

Arterial

supply(79. ml:min)

;enousreturn

!roimal

tubule

Distaltubule

6oop of 'enle

Collecting

tubule

8rine

(7*-l:day)

lomerulus

Active secretion

Reabsorption

4*g* gentamicin0 cephalein

http://www.wits.ac.za/fac/med/pharmacy/bio-elim.ppthttp://www.wits.ac.za/fac/med/pharmacy/bio-elim.ppt


20/33

Absorption !hase

&rea =nder the $urve

Cma

Rat plasma Con&entrations of '() **+**** after

, m"-k"oral

administration to rats

1ime (h)

. / 0 1

3 A 2

< < $ < < < < ( u g : l )

.

/...

0...

1...

2...


21/33

8istribution

"lasma $on.entration vs Time

'() **+**** after / m"-k" %; administration to rats

1ime (h)

. /. 0. 1. 2. 3..

3 A 2

< < $ < < < < ( u g : l )

.

3....

/....

4....


22/33

4limination

Semi3%og "lot

'() **+**** after / m"-k" %; administration to rats

1ime (h)

. /. 0. 1. 2. 3..

3 A 2

< < $ < < < < ( u

g : l )

3

3.

3..

3...

3....


23/33


24/33

Oral availability

http:>>www.icp.org.nz>html>oral?availablity.html

'ioavailabilit$5 the 6 of an in"esteddose of a dru" that enters s$stemi&

&ir&ulation

www.icp.org.nz

http://www.icp.org.nz/html/oral_availablity.htmlhttp://www.icp.org.nz/html/oral_availablity.htmlhttp://www.icp.org.nz/html/oral_availablity.htmlhttp://www.icp.org.nz/html/oral_availablity.html


25/33

8ioavailability: implications for oraland parenteral dosing

• 3igh bioavailability, dose same for and po routes

• %ow bioavailability, lower dose forparenteral than po routes


26/33

8ioavailability after oral administrationof dierent formulations

'urkitt, (ustralian Pres&riber, /..4


27/33

8ioe)uivalence

• "harmaceutically e)uivalent and e)ualsystemic bioavailability

•


28/33

($A ( B 8: Therapeuticigni1canceC


29/33

($A ( B 8: 8 neective

78C

78C 9 7inimum 8ffe&tive Con&entration


30/33


31/33


32/33


33/33

yarat Obat

• Duality>2ara#teristi#

• (man

•+fe#

the principle of pharmacokinetic

Documents