THE PRINCIPLES OF

PHARMACOKINETIC
Novi Irwan Fauzi
KK Farmakologi
Oktober 2015

Sekolah Tinggi Farmasi

Indonesia
novi.irwan.apt@gmail.com

@OppieFauzi

Absorption

Taken from TNO Pharma Web

Most Drugs administered orally as

pills
Absorbed largely from small
intestine
Some Sublinqual absorption
Rectal Absorption (suppository)
Some Absorption from stomach
(rare)
Molecules need to be near the
intestinal mucosa to be absorbed
Compound should be soluble in
gut contents or in vehicle
Crystals are not well absorbed
Gummy stuff is not well absorbed

Movement of drugs across cell

membranes

Fulton, UCSF

Membranes
Types of Membranes:
Cell Membranes: This barrier is permeable to many
drug molecules but not to others, depending on their
lipid solubility. Small pores, 8 angstroms, permit small
molecules such as alcohol and water to pass through.
Walls of Capillaries: Pores between the cells are
larger than most drug molecules, allowing them to
pass freely, without lipid solubility being a factor.
Blood/Brain Barrier: This barrier provides a
protective environment for the brain. Speed of
transport across this barrier is limited by the lipid
solubility of the psychoactive molecule.
Placental Barrier: This barrier separates two
distinct human beings but is very permeable to lipid
soluble drugs.

Anatomy of the intestines

Anatomy of the intestines

Absorption at brush border cells

Taken from Camitro Web Site

Passive transcellular thought to be major route

Non-charged compounds diffuse best

Mekanisme Umum Obat Lintas

Membran
Passive Transport
Paracellular
Transcellular: Difusi Pasif Langsung
Difusi Pasif Terfasilitasi (Aquaporin,
kanal ion, dll)

Active Transport
Endositosi dan Eksositosis

Drug Distribution

Dependent upon its route of administration and target area,

every drug has to be absorbed, by diffusion, through a
variety of bodily tissue.
Tissue is composed of cells which are encompassed within
membranes, consisting of 3 layers, 2 layers of water-soluble
complex lipid molecules (phospholipid) and a layer of liquid
lipid, sandwiched within these layers. Suspended within the
layers are large proteins, with some, such as receptors,
transversing all 3 layers.
The permeability of a cell membrane, for a specific drug,
depends on a ratio of its water to lipid solubility. Within the
body, drugs may exist as a mixture of two
interchangeable forms, either water (ionizedcharged) or lipid (non-ionized) soluble. The
concentration of two forms depends on characteristics of
the drug molecule (pKa, pH at which 50% of the drug is
ionized) and the pH of fluid in which it is dissolved.
In water soluble form, drugs cannot pass through
lipid membranes, but to reach their target area, they

Protein Binding

Reversible and rapid

Depends on [free drug], affinity for binding sites, [protein]

Protein binding
Many drugs bind to plasma proteins
Albumin (acidic drugs, eg warfarin,
NSAIDs)
Alpha-1 acid glycoprotein (basic drugs,
eg quinine)
Lipoproteins (basic drugs)
Globulins (hormones)

Only free drug can bind to receptors

Plasma Proteins that Bind

Drugs
albumin: binds many acidic drugs
and a few basic drugs
-globulin and an 1acid
glycoprotein have also been found
to bind certain basic drugs

Metabolism
Metabolism occurs in liver, gut wall, lungs,
kidneys and other organs:
Phase I:
Hydroxylation
Dealkylation
Sulfoxide and Nitroxide formation
etc.
Phase 2 (Conjugation)
Glucuronide formation
Sulfation
Glutathione Conjugation
Cysteine Conjugation
Acetylation
etc.

Metabolism

Liver is the major metabolizing organ in the body:

Removes toxic substances and drugs from the blood.
Cytochrome P450s are the major drug metabolizing
enzymes, they are found in every organ in the body.
The body generally makes compounds more polar so
they are more readily excreted in the kidney.

Cytochrome P450 in Rat and Man:

Species Differences

Proportion of Drugs
Metabolized
by the Major CYPs
CYP 2C

CYP 2D6

CYP 1A2
CYP 2E1

CYP 3A

Drug - Drug Interactions

Risks associated with CYP enzyme inhibition or induction
Inhibition of CYP
enzymes

Decreased degradation
of comedicated drugs

Increased drug plasma

concentrations

Risk of severe
adverse events

Induction of CYP
enzymes

Increased degradation
of comedicated drugs

Decreased drug plasma

concentrations

Loss of pharmacological
effect

Risk of severe
secondary effects

Routes of Excretion
Metabolism
in Liver
Drug in
Intesti
ne

Absorption

Betaglucuronidase

Excretion
in
Feces

Drug in
Portal
Blood

Conjugates
Phase-1
Bile

Conjugate
s
in
Intestines

Drug in
Blood

Excretion
in
Urine

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

Renal excretion
excretion
Renal

Arterial
supply
(130 ml/min)

Proximal
tubule

Collecting
tubule

Venous
return

Distal
tubule

Active secretion
Urine
(1.5l/day)

Reabsorption
E.g. gentamicin, cephalexin
Loop of Henle

Area Under the Curve

Rat plasma Concentrations of BAY XX-XXXX after
5 mg/kg oral administration to rats
Cmax

BAY XX-XXXX (ug/l)

8000

6000

4000

2000

0
0

Absorption Phase

Time (h)

Plasma Concentration vs. Time

BAY XX-XXXX after 2 mg/kg IV administration to rats

BAY XX-XXXX (ug/l)

30000

Distribution

20000

10000

0
0

20

40

Time (h)

60

80

100

Semi-Log Plot
BAY XX-XXXX after 2 mg/kg IV administration to rats

BAY XX-XXXX (ug/l)

10000

Elimination

1000

100

10

1
0

20

40

Time (h)

60

80

100

Oral availability
http://www.icp.org.nz/html/oral_availablity.ht
ml

Bioavailability: the % of an ingested

dose of a drug that enters systemic
circulation

www.icp.org.nz

Bioavailability: implications for oral

and parenteral dosing
High bioavailability, dose same for IV
and po routes
Low bioavailability, lower dose for
parenteral than po routes

Bioavailability after oral administration

of different formulations

Burkitt, Australian Prescriber, 2003

Bioequivalence
Pharmaceutically equivalent and equal
systemic bioavailability
Generics
must be bioequivalent to innovator (80125%)

AUC A > B: Therapeutic

Significance?

AUC A > B: B Ineffective

MEC

MEC = Minimum Effective Concentration

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