Pharmacokinetics

Chapter 3: First effect

Number of credit : 3
Number of hour : 45h Academic year :2018-2019
 First effect

Step 1: Administration
–First pass effect
–Bioavailability
Step 2: Distribution
Step 3:
–Metabolism
–Elimination
 First pass effect

I. Definition
➔ Loss of drug by metabolism
before it reaches the
systemic circulation, from
its first contact with the
body responsible for its
biotransformation.
 First pass effect
II. Routes of administration of drugs & Metabolism
1. Intra arterial (reference route)
Exception for human clinical: drug
instantly into the general circulation ⇒
100 % of the administered dose
available

2. Intravenous route
Pass in the lungs before arrival into the
general circulation ⇒ potential metabolic
effect of pulmonary first pass.
 First pass effect
II. Routes of administration of drugs & Metabolism
3. Oral route
Before reaching the systemic
circulation, the drug must pass through
various physiological systems :

- Intestinal mucosa (presence of enzymes

possible metabolism) ⇒first-pass
intestinal effect
- Liver : Major site for biotransformation
,real metabolites factory ⇒first-pass
hepatic effect
- Lung ⇒ first-pass pulmonary effect
 First pass effect
II. Routes of administration of drugs & Metabolism

4. Rectal route
- By review the anatomy of rectum,the 3 types
of vein integrate in rectum involved of drugs
resorption :
1) Inferior rectal vein
2) Middle rectal vein
3) Superior rectal vein
 First pass effect
III. First-pass hepatic effect and clinical application
➔ Process by which the drug absorbed orally undergoes metabolism
and / or elimination more or less at the liver before it reaches the
systemic circulation

➔ First-pass effect and impact on therapeutic response

● Loss drug should result in loss of therapeutic effect. Therefore
induce an adverse effect.
● Sometimes we observed the appearance of active metabolites ⇒
increased therapeutic effect
Ex : Imipramine , Diazepam ...
 First pass effect
III. First-pass effect & clinical consideration
1. All drugs has first-pass effect are general bad for therapeutic effect ?

Liver metabolism

O-Demethylation
(CYP2D6)

Codeine Morphine

Colonic bacteria

Azoreductase
 First pass effect
III. First-pass effect & clinical consideration
2. The drugs of the same groups has the same first-pass effect ?

- Extensive first pass effect

- Intermediate first pass effect 17% 41%
- Poorly first pass effect
42%

5-8%
Glucuronides
Atenolol
Hydroxylation

35% to 40%
Pindolol ethereal sulfates
 First pass effect
III. First-pass effect & clinical consideration
3. First-pass effect depend on dose administration ?

http://www.icp.org.nz/icp_t9.html
 First pass effect
III. Nature of the first pass effect
➔ At the lungs
● Reaction : oxidation, reduction, dealkylation, hydrolysis, sulfation.
● Ex. Nortriptyline, Prostaglandins,…
Type Reaction Type Reaction

Aryl-Hydroxylation Reduction Nitro-reduction

Alkyl-Hydroxylation Hydrolysis Amide

N-dealkylation Acetylation
Oxydation
O-dealkylation Methylation
Other -reaction
N-oxidation Sulfoconjugation

N-hydroxylation
 First pass effect
III. Nature of the first pass effect
➔ At the intestine
● Intestinal flora
- Reaction: Dealkylation, Glucuronide and Sulfation, Decarboxylation,
Reduction of nitro compounds by anaerobic microorganisms.
● Intestinal mucosa
Similar enzyme to the liver; but weaker activity.
Reaction: oxidation, reduction, hydrolysis, glucurono and sulfation.
Ex: Aspirine, Flurazépam, Morphine, Isoprénaline, L-Dopa
➔ At the intestine
Reaction Substrates

Glucuronic conjugation

Sulfidation metabolite

Hydrolyse Amino acid conjugation

Acetylation conjugation

Esters

Functional group :
- Nitro
Reduction
- Azo
- Carbonyle

Decarboxylation Aromatic acid

Dealkylation Methyl group of N , O

Acetylation Aliphatic amines

 First pass effect
III. Nature of the first pass effect

➔ At the liver
● Intense and extensive metabolism
● Most biotransformations occur in the endoplasmic reticulum due
microsomes (many enzyme systems)

http://www.icp.org.nz/icp_t6.html
➔ At the liver
Reactions Enzymes Drugs

Oxydation
C & N hydroxylation
Phenytoin , Babituric , chlordiazepoxide
N & S oxidation Cytochrome P-450
,Antihistamine
Dealkylation
Deamidation

Reduction Chloramphenicol
Flavoproteins
Nitro

Hydrolysis Esterase Procaine, Indomethacin

Amidase

Methylation Catechol-O-methyltransfe Isoprenaline

rase

Acetylation N-acetyltransferase Isoniazid

 First pass effect
III. Nature of the first pass effect R-H General circulation

➔ Biliary Excretion R-H Liver

● Some drugs produce an Biliary elimination

R-H
enterohepatic cycle R-conjuguated
● Create , for example , in the Intestinal mucosa
liver, the conjugates of Duodenum
large molecular size which
R-H
are eliminated in the bile. R-conjuguated
Intestinal flora

Hydrolysis
 First pass effect
Para = 500mg =100%, administration
IV. Evaluation of first pass effect E1 = 0.3%
Eh = 0.4%
Ep = 0.1%
● The first-pass effect leading to a decrease in circulating levels of a drug
● This results in a decrease in AUC of plasma or blood concentration.

➔ This effect corresponds to a sum of

extraction coefficients:
E = E i + Eh + E p
Eh : hepatic extraction coefficient
Ei : intestinal extraction coefficient
Ep : pulmonary extraction coefficient

http://www.icp.org.nz/icp_t6.html
 First pass effect IV - 100% no metabolism
Oral - intestinal + Liver
IV. Evaluation of first pass effect
➔ Estimate of first pass effect by area under the plasma
concentration of drug

E = (AUCiv – AUCoral )/ AUCiv

= 1- AUCoral/AUCiv

● First pass effect : Ei + Eh ( Ep ≈ 0)

If we include of % absorption (f) , we can estimate of

first pass effect

E = 1- AUCoral/AUCiv x 100/f
Intestinal metabolism Liver metabolism
http://www.icp.org.nz/icp_t6.html
 First pass effect Trapezoid methode

IV. Evaluation of first pass effect

➔ Estimate of first pass effect by area under
the plasma concentration of drug

● From 0 to t :
AUC0 →t = [(C0+C1)/2]x(t1-t0) + [(C1+C2)/2]x(t2-t1) + … + [(Cn-1+Cn)/2]x(tn-tn-1)

n
AUC0→t = ∑ [(Ci+Ci+1)/2]x(ti+1-ti)
i =0

● From 0 to t :
AUCt→∞ = Cn x Ke
Ke : constant elimination rate of studied drug in the last phase
Cn : value of the last measured concentration
 First pass effect
[ ]
IV. Evaluation of first pass effect
➔ Estimate of first pass effect by area under
the plasma concentration of drug
0 t time
● From 0 to t :

AUC0 →t = [(C0+C1)/2]x(t1-t0) + [(C1+C2)/2]x(t2-t1) + … + [(Cn-1+Cn)/2]x(tn-tn-1)

n
AUC0→t = ∑ [(Ci+Ci+1)/2]x(ti+1-ti)
i =0

● From 0 to t :
AUCt→∞ = Cn x Ke
Ke : constant elimination rate of studied drug in the last phase
Cn : value of the last measured concentration
 First pass effect
IV. Evaluation of first pass effect
➔ Practice : Time Concentration IV

0.083 7.8

0.25 6.9

0.5 6.25

1 5.7

2 4.65

4 3.95

6 -

8 2.3

Calculate the AUC0→∞ 10 1.65

Kel (iv) = 0.132 12 1.35

18 -
References
- Sunil S Jambhaekar and Philip J Breen ; Basic Pharmacokinetics , 2 nd
edition, 2012.
- Tomas N.Tozer and Malcolm Rowland ; Essential of Pharmacokinetics and
Pharmacodynamics, 2nd edition, 2016.
- Leon Shargel and Andrew B.C YU ; Applied Biopharmaceutics and
Pharmacokinetics ,7th edition ,2016
- Tarek A.Ahmed ; Basic Pharmacokinetics concepts and Some Clinical
Applications,2015
- Sara E. Rosenbaum ; Basic pharmacokinetics and Pharmacodynamics,2 nd
edition, 2017.
- Robin Southwood , Virginia H.Fleming and Gary Huckaby ; Concepts in
Clinical Pharmacokinetics . 2018