12/30/2010

METABOLISME

dr. Yunita Sari Pane

DEPARTMENT OF PHARMACOLOGY AND THERAPEUTIC

UNIVERSITAS SUMATERA UTARA

Pharmacokinetic

•absorption
•distribution
•BIOTRANSFORMATION
•elimination

1
 12/30/2010

Intravenous
Administration

Oral
Administration

Metabolism Liver

Intestines

GI: Biliary-
Biliary-Fecal Route

liver

bile
blood

gall bladder

GI track
Enterohepatic cycle

2
 12/30/2010

GI: Biliary-
Biliary-Fecal Route

lipid soluble drugs have prolonged

effects

Oral Drugs

enter stomach:
stomach: highly acidic
environment

absorbed by GI tract into portal
circulation of the liver
• first
first--pass effect

3
 12/30/2010

First Pass Effect

pass through
liver before
reaching
circulation

undergo
metabolism
by liver

Biotransformation

chemical alteration of drug

4
 12/30/2010

Biotransformation

change
• size
• lipid solubility
• charge or polarity

Sites of biotransformation

liver: greatest activity

others
• intestines, kidneys, brain, &
plasma

5
 12/30/2010

Factors Affecting
Biotransformation

Age

very young
• less developed enzyme system
• less developed blood brain
barrier

very old
• decreased GI absorption
• decreased renal clearance

6
 12/30/2010

Disease

altered liver enzymes
• liver disease
– most decrease enzymes

– some may increase

Disease

other diseases that decreased
liver enzymes
• hypothyroid
• hypoxemia
• malnutrition

7
 12/30/2010

Other

genetic alterations or defects in
enzymes
• metabolize drug more slowly or
more rapidly

Biotransformation

8
 12/30/2010

Decreased Activity of Liver Enzymes

decreased rate of biotransformation

can result in toxic effects

Metabolism
(Biotransformation)

Two effects
• Transformation to less active
metabolite
• Enhancement of solubility

Liver = primary site

Liver disease
• Slows metabolism
• Prolongs effects

9
 12/30/2010

Hepatic ‘First-
‘First-Pass’
Metabolism

Affects orally administered drugs

Metabolism of drug by liver
before drug reaches systemic
circulation

Drug absorbed into portal
circulation, must pass through
liver to reach systemic circulation

May reduce availability of drug

Elimination

Elimination

Excretion Drug Metabolism

(Biotransformation)

10
 12/30/2010

Drug Metabolism

The chemical modification of drugs
with the overall goal of getting rid
of the drug

Enzymes are typically involved in
metabolism
Metabolism Excretion
Drug More polar
(water soluble)
Drug

ABSORPTION METABOLISM ELIMINATION

Phase I Phase II

Drug Conjugate

Drug metabolite with Conjugate

modified activity
Drug

Inactive drug Conjugate

metabolite

Drug

Lipophilic Hydrophilic

11
 12/30/2010

METABOLISM REACTION

I. PHASE - I
- Oxidation : Morphin,
acetaminophen
- Reduction : Chloramphenicol,
Clonazepam
- Hydrolisis : Aspirin, Lidocain

METABOLISM REACTION

II. PHASE-
PHASE- II
- Conjugation : Morphin
(process glucuroridation),
INH (process acetilation),
etc.

12
 12/30/2010

Sites of Drug Metabolism

Metabolism occurs in many
tissues

E.g. brain, kidney, lung

But mostly in the liver because …
all of the blood in the body
passes through the liver.

Consequences Of Metabolism

Drug metabolism != Drug

inactivation

The metabolite may have
 Equal activity to the drug
 No or reduced activity
 Increased activity (Prodrugs)
 Toxic properties

13
 12/30/2010

METABOLISM KINETIC

1.First order kinetic
if drugs lower doses 
metabolism rapidly.

2.Zerro order kinetic
if drugs higher doses 
metabolism slowly.

The Most Important Enzymes

Microsomal cytochrome P450

monooxygenase family of enzymes,
which oxidize drugs

Act on structurally unrelated drugs

Metabolize the widest range of
drugs.

14
 12/30/2010

Alteration in “first pass metabolism”

• (note: high clearance

drug have > 30%
extraction from hepatic
blood (F < 0.7))
• a drug that inhibits
hepatic metabolism will
increase bioavailability of
high clearance drug
(provided it is
metabolised by the
enzyme(s) inhibited) and
vice--versa
vice

Examples:

– cimetidine inhibits CYP450s,

therefore doubles oral
propranolol bioavailability
– phenytoin induces enzymes,
therefore decreases felodipine
bioavailability
– acute alcohol intake inhibits a
CYP, therefore amitriptiline
bioavailability is higher

15
 12/30/2010

Enzyme Inhibition
• (drugs that reduce hepatic blood flow
also inhibit metabolism of high
clearance drugs)

• if this metabolic route is a major

pathway of elimination, drug kinetics
will change (increase Css and T(1/2))
and therefore drug response will
change

• enzyme inhibition is immediate, and on

cessation of inhibitor, reversion to
normal is immediate

• examples:
– metronidazole decreases
clearance of warfarin by 40%
– cimetidine decreases clearance
of phenytoin by 35%
– propranolo decreases clearance
of lignocaine by 50% (by
reducing hepatic blood flow)
– omeprazole decreases clearance
of warfarin

16
 12/30/2010

examples with regards to enzymes other

than cytochrome P450s

• example 1: allopurinol
– is a xanthine oxidase inhibitor
(used as an anti-
anti-gout agent)
– also inhibits metabolism of
cytotoxic agent 6-
6-
mercaptopurine (6-(6-MP)
– therefore concurrent use of
allopurinol and 6-
6-MP leads to
elevated plasma levels of 6-
6-MP
and toxicity

• example 2: disulfiram
– inhibits aldehyde
dehydrogenase
– therefore is used to give
alcoholics a nasty "aldehyde
reaction" when they take
alcohol

17
 12/30/2010

Alteration of liver blood flow:

• for high first pass clearance

drugs only, a fall in liver blood
flow will cause a clear reduction
in systemic clearance
• example: lignocaine toxicity can
occur when patients are given a
beta--blocker which reduces
beta
liver blood flow

Importance

 Toxic drugs may accumulate

 Useful drugs may have no
benefit because doses are too
small to establish therapy
 A drug can be rapidly
metabolized.

18
12/30/2010

19