Pharmacy and Biotechnology

Department of Pharmaceutical Technology 1

Biopharmaceutics &
Pharmacokinetics
[PHTC 521]
LECTURE 3: “DRUG DISTRIBUTION, METABOLISM AND
PHARMACOGENETICS”
COURSE INSTRUCTORS:
DR. SHAHIR AZIZ
DR. SALMA TAMMAM

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Lecture Outline 2

 Factors affecting Drug distribution

 Organ Size
 Drug Partitioning
 Blood Flow
 Drug-Protein binding

 Hepatic Metabolism
 Pharmaco-genetics
 Bioavailability recap - Practice problems

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Oral Target
3
Tissue /
Medication Organ Stomach

Parenteral
Medication

Hepatic circulation

Small
intestine
Heart
Liver

Liberation
Absorption
Distribution
Metabolism Large
intestine

Excretion Distribution by Blood Circulation

Toxicity
Dr. Shahir Aziz – (PHTC 521) – Winter 2021
 Drug Distribution and Metabolism
4
Drug input into the systemic circulation
For Orally administered drugs, Which occurs first;
Metabolism or Distribution ?!

Blood
First Pass Effect Distribution Elimination
to Tissues
and
Initial Dose
GIT Hepatic Organs Hepatic Other Tissue Urinary
Metabolism Metabolism Metabolism metabolism Excretion

Dose Fraction available for distribution (F) = Un-metabolized drug fraction

1 – [Extraction Ratio of GIT (EG) + Extraction ratio of Liver (EH)]

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
5
Factors Affecting Drug Distribution

 The majority of drugs relay on passive delivery to the site of action

through distribution by the vascular system

 Upon reaching the general circulation, the drug is diluted in the

blood volume which influence its activity at the site of action

 The apparent volume of distribution (VD) relates the amount of

drug in the body to the measured blood/plasma concentrations

𝑎𝑚𝑜𝑢𝑛𝑡
𝑣𝑜𝑙𝑢𝑚𝑒 =
𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
6
Factors Affecting Drug Distribution

1. The size of the Organ into which the drug distributes

2. The Partition coefficient of drug between Organ and the blood

3. The Blood Flow to the distributing organs

4. The Extent of Drug - Protein Binding in plasma and in tissues

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
7
Factors Affecting Drug Distribution
A) Organ size, Blood flow and Partition coefficient
Examples of average Volumes and blood supplies of different body organs for a standard 70 Kg man (Table
adapted from Chapter 5, Modern Pharmaceutics Volume 1: Basic Principles and Systems, Fourth Edition)

Volume of Blood in Blood flow /

Tissue Volume Blood flow
Tissue/Organ equilibrium with tissue Tissue
(ml) (ml/min)
(ml) (ml/100ml)
Adrenals 20 62 100 500
Kidneys 300 765 1240 410
Thyroid 20 49 80 400
Heart 300 148 240 80
Liver 3900 979 1580 41
…………………...………… ……………………………………. …………………………………………………………………. ………………………………………. ……………………………………

4 L blood in equilibrium
Total 70 L of all tissues with tissues + 1.4 L
arterial blood

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
8
Factors Affecting Drug Distribution
A) Organ size, Blood flow and Partition coefficient

 The blood flow per unit volume of tissue indicates how fast (Rate) a drug can be
delivered to a specific body region (tissues).

 How much drug can be stored (Extent) or distributed inside the tissue can be reflected
by the size of the tissue and the ability of the drug to diffuse into the tissues from the
blood inside the organ.

 The Partitioning of the drug (Partition coefficient) between organ and blood = KO/B

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
9
Factors Affecting Drug Distribution
B) Drug – Protein Binding
 Drug interact with plasma and tissue protein forming
Drug-macromolecule complex Free Drug Absorbed
into blood

 This complex can be either Reversible or Irreversible

P Plasma
P
P P

 Irreversible binding (by covalent chemical bonding) can

Unbound drug Bound drug -Protein
lead to reactive chemical intermediates that cause
certain tissue toxicity (e.g.: Hepatotoxicity by high
acetaminophen dose that interacts with liver proteins)

 Reversible binding occurs by weak bonds (i.e.: hydrogen bonds or van der Waals forces) that
cause restrictions to the drug distribution kinetics

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
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Factors Affecting Drug Distribution
B) Drug – Protein Binding
 Major Proteins to which drug binds:
a) Albumin (MW = 65 KDa)
b) 1- Acid Glycoprotein (MW = 44 KDa)
P Plasma
c) Lipoproteins (i.e.: VLDL, LDL, HDL) P
P P

d) Erythrocytes (RBCs)
Unbound drug Bound drug -Protein

 The Extent of drug protein binding in plasma or tissue, affects the VD:
 Highly Bound Low fraction of free active drug (Fu = unbound fraction)
 Generally, The higher the (Fu) the easier the drug diffusion into tissues

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
11
Factors Affecting Drug Distribution
B) Drug – Protein Binding
 Determining Factors of Protein Binding:
I. The drug: Physicochemical properties and
concentration in body
P Plasma
II. The Protein: Quantity and nature (type) P
P P
III. The affinity between the drug and protein
Unbound drug Bound drug -Protein
IV. Drug interactions:
• Competition for the drug by other substances binding to same protein active site
• Alterations of the protein made by other substances, changing the drug affinity
V. The Pathological condition of the patient (e.g.: hepatic diseases affects drug-protein
binding)

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
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Hepatic Metabolism
 Metabolism; is the biotransformation of a drug into
a metabolite by enzymatic conversion.

 The rate of metabolism is determined by both the

enzyme concentration and the drug concentration.

 The liver is the major organ for drug metabolism

due to the abundancy of metabolic enzymes.
However, intestinal tissues, Lungs, Kidneys and the
Skin also contain considerable amounts of
metabolic enzymes
Liver anatomical diagram

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
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Hepatic Metabolism
A) Enzyme Kinetics

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
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Hepatic Metabolism
B) Metabolism Pathways
 Cytochrome P450 is a family of isozymes responsible for the
biotransformation of several drugs via oxidation
 Biotransformation can either deactivate a drug (i.e.: metabolite
is inactive)or activate an inactive drug (i.e.: metabolite is the
active form)
 Biotransformation is divided into:
A. Phase I Reactions B. Phase II Conjugation:
I. Oxidation I. Glucuronide conjugation
II. Reduction II. Sulfate conjugation
III. Hydrolysis III. Methylation
IV. Acetylation

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Drug Distribution and Metabolism
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Hepatic Metabolism
C) Factors Affecting Drug Metabolism
 Drug – Drug Interaction:
 Enzyme Induction: the chemical stimulated increase in the enzyme activity (i.e.:
Concentration) by another drug
 Enzyme Inhibition: either direct inhibition of metabolizing enzymes or due to
competitive substrates

 Genetic variation of Cytochrome P-450 (CYP) Isozymes:

 Exists in many forms among individuals due to genetic differences
 The substrates specificities of the P-450 depends on; the nature, size, polarity
and charge of the amino acids forming the enzyme.

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Pharmacogenetics
16
Overview
 The study of genetic variation among individuals that
affects the response to medicine

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Pharmacogenetics
17
Overview
 The Goal is to Personalize the drug therapy achieving greater efficacy and
safety

 Pharmacogenomics involves study of the role of genes and their genetic

variations (DNA, RNA level) in the molecular basis of disease, and therefore, the
resulting pharmacologic impact of drugs on that disease

 Application of pharmacogenetics to pharmacokinetics and pharmacodynamics

helps the development of models that predict an individual's risk to an adverse
drug event and therapeutic response

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Pharmacogenetics
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Overview
 Pharmacogenetics and pharmacogenomics are both important disciplines involved in
the study of genes that code for drug-metabolizing enzymes, drug receptors, drug
transporters, and ion channels or efflux systems.

 Example: The “monoclonal antibody Herceptin” was designed to treat a subset of

breast cancer patients who overexpress the HER-2 (human epidermal growth factor
receptor-2) gene. Patients who lack HER-2 overexpression are considered to be non-
responders to Herceptin therapy. In the past, such differences would be apparent only
after a trial-and-error period. This genetic knowledge improves our ability to select or
design the proper drug for individuals suffering from a disease with a varying range of
molecular defects.
Dr. Shahir Aziz – (PHTC 521) – Winter 2021
 Bioavailability & Bioequivalence
19
Recap - Practice Problems
 Guidance for industry
Comparing Extent & Rate to check of oral formulations are bioequivalent

 Guidance for Clinical

Converting from intravenous (IV) to oral (PO) therapy as soon as patients
are clinically stable can reduce the length of hospitalization, reduce the risk
of infection and lower associated costs.

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Bioavailability & Bioequivalence
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Guidance for industry
Which to use?
1. Paracetamol 500mg only
2. Effervescent Paracetamol
500mg
3. Paracetamol 500mg with
sodium salts (advance
“Optizorb”)
1. Paracetamol 500mg with
65mg caffeine
2. Effervescent Paracetamol
500mg with 65mg caffeine
3. Paracetamol 500mg with
65mg caffeine & sodium
salts (advance “Optizorb”)

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Bioavailability & Bioequivalence
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Guidance for industry

Liu et al., J Bioequiv Availab 2011, 3:11

DOI: 10.4172/jbb.1000095
Dr. Shahir Aziz – (PHTC 521) – Winter 2021
 Bioavailability & Bioequivalence
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Guidance for Clinical practices
Treatment-related Example:
Conversion from IV infusion to Oral dosing
Practical Example 1

• An adult male asthmatic patient (age 55, 78 kg) has been maintained on an IV
infusion of aminophylline at a rate of 34 mg/hr.
• The steady state theophylline drug concentration was 12 µg/mL and total body
clearance was calculated as 3.0 L/hr.
• Calculate an appropriate oral dosage regimen of theophylline for this patient.
• Given: Aminophylline is a soluble salt of theophylline and contains 85% theophylline
(S=0.85)
• Theophylline is 100% bioavailable (F = 1) after an oral dose.

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Bioavailability & Bioequivalence
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Guidance for Clinical practices
Treatment-related Example:
Conversion from IV infusion to Oral dosing
Practical Example 1 • total body clearance
(ClT ) = kVd
 Oral theophylline dose rate
 = SFD0 / τ = (0.85) (1) (34) / 1 = 28.9 mg / hr
 Therefore the total daily dose is 28.9 mg/hr x 24 hr
or 693.6 mg/day
 Possible oral theophylline schedules might be 700
mg/day or 350 mg every 12 hours

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

 Bioavailability & Bioequivalence
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Guidance for Clinical practices
Most common dosing problem 

Dr. Shahir Aziz – (PHTC 521) – Winter 2021

REFERENCES: 25

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