Biopharmaceutics

Bappaditya Chatterjee
GSP, GITAM University
This lecture will cover….
Elimination I (UNIT 3)
■ Metabolism and role of liver
■ Phase I and phase II enzymatic reaction
■ Factors affecting protein binding
■ Hepatic clearance
A drug’s action: Onset and duration

• Absorption • Distribution or re-

• Distribution to tissue/ distribution to tissue
target site • Rate of elimination

What is
• Metabolism the
• Excretion requirement
of
metabolism ?
Metabolism/Biotransformation
■ 4 types of product (metabolite)
1. Active drug → inactive metabolite
2. Active drug → active metabolite
– E.g. codeine → morphine
3. Inactive drug to active metabolite
– E.g. sulfasalazine → sulfapyridine + 5-aminosalicylic
acid
4. Active drug → reactive intermediate
– E.g. paracetamol → N-acetyl-p-benzoquinoneimine
Metabolism/Biotransformation

Major places:
Liver> Lungs> Kidney> Intestine> Placenta> Adrenal> Skin

Points to remember on liver in metabolism:

1. Hepatocytes are the main site
2. Transporters are present
3. Heterogenecity of the liver is significant.

Major enzymes:
1. Microsomal
2. Non-microsomal
Hepatic metabolism (Phase I)

Main objective: To impart hydrophilicity to the metabolite

Oxidative reaction
• To induce polar hydrophilic group such as –OH
• Enzyme involved – mixed functional oxidase (mono oxygenase/ MFO)
• Multifunctional mixed enzyme system – Cytochrome P 450 family +phospholipid
• Different type of oxidative reaction may happen – oxidation of aromatic carbon
oxidation of C=C bonds
oxidation of aliphatic carbon
oxidative dealkylation
oxidative deamination etc.
Also “MAO” dependent metabolism
Hepatic metabolism (Phase I)

Reduction reaction
• To reduce C=C bond or alcoholic group
• Reduction of nitro or azo compound
• Reductive dehalogenation

Example:
Nitrazepam to 7 amino metabolite
Halothane to tri fluoro metabolite
Hepatic metabolism (Phase I)

Hydrolysis reaction
• Reduction of ester, ether, amide etc
• Enzyme involved – esterase type
• Breaks large molecule in smaller groups
• For example- Clofibrate to free acid (active)
Aspirin to salicylic acid (active)
 Hepatic metabolism (Phase II)
Main objective: To generate more water soluble group by covalent attachment of small
polar molecule to either unchanged drug or to phase I product
• Real drug detoxication pathways
• Glucuronide conjugation is the major mechanism
• Involves activation of the substrate or the conjugating agent Eg; UDPGA
• Capacity limited
• Rute of excretion depends on the molecular weight of the conjugate
• D glucuronic acid conjugation, amino acid conjugation, sulphation and
glutathione conjugation are predominant
• Acetylation of primary amine containing drug , Eg. histamine

Example:
Salicylic acid to salicyluric acid with glycine as conjugating agent
Morphine to Morphine O glucuronide
Factors affecting biotransformation
1. Physicochemical property of the drug - ???
2. Induction of metabolizing enzyme

• By some inducer such as phenobarbital

• By increase in liver blood perfusion
• By increase in enzyme stability
• By increase in CYT P450 synthesis
• Auto-induction is there
Factors affecting biotransformation
3. Inhibition of metabolizing enzyme

Direct inhibition
Which one
Indirect inhibition is
a. Competitive – by
structurally More significant
a. Decrease in
similar
enzyme content in terms of toxicity,
compound(methac Inhibition
b. Nutritional or
holine and Ach) Or
hormonal
b. Non-competitive-
any dissimilar
imbalance Induction ??
compound (INH
inhibits Phenytoin)
c. Product inhibition
 Factors affecting biotransformation
4. Biological factors

Genetic difference –
Pharmacogenetics – Study of inter subject variability in PK and PD including
elimination at the genetic level
Ethnic variation - common

Sex difference – Brahmankar BioPharm, Pp 187

Not many studies, most effect occurs during or after puberty due to changes in sex
hormones
 Factors affecting biotransformation
4. Biological factors

Age difference –
In Neonates – under developed enzyme system,
In aged – microsomal activity reduced
Diet–
Low protein diet decreases metabolic activity.
Fat free diet also decreases metabolic activity.
Starvation results in decreased glucuronide conjugation
Liver extraction ratio (ER)

5)

Where, Ca = drug concentration in blood entering liver

Cv = drug concentration in blood leaving the liver “Propanolol
has an ER of
Ca >>> Cv, so ER should be always less than 1. 0.7” means…
Liver extraction ratio (ER)
6) CL = Q * ER

Where, Clh = Clearance of drug from liver Unit of

clearance
= Volume of blood passing through liver that is
cleared of the drug per unit time
Liver extraction ratio (ER)

A drug having high ER (>0.7), having CLh ≈ Q

A drug having low ER (>0.3), having CLh << Q

1. A drug, ‘X’ has hepatic clearance of 6 L/Hr. If total blood flow to the liver is 1.2
L/min, then calculate the extraction ratio of the drug.

2. A drug enters the liver at a concentration of 0.6 mcg/ml. It is assumed that 40 % of

the drug has been metabolized by the liver. If total hepatic blood flow is 1.2 L/min,
then calculate the hepatic clearance per hour.

3. After absorption a drug enters liver at a concentration of 0.9 mcg/ml and after
metabolism the concentration of the drug in the blood leaving liver is 0.3 mcg/ml.
If the hepatic clearance value of the drug is 12 L/hr, then how much is the liver
blood flow for that patient?
Biopharmaceutical Drug Disposition Classification
System (BDDCS)
Reference
• BioPharm, Brahmankar
• App BioPharm, Shargel, Chapter 4 & 11