MPC350:

PHARMACOLOGY &
THERAPEUTICS
 Professor Christian
Chinyere Ezeala
DLitt et Phil, PhD, MSc, FHPE, DMLS,
AMLSCN, MRACI, CChem, MRSB,
CBiol, MICR, CSci, FASI, MRSNZ
 LECTURE 2:
PHARMACOKINETICS 1

Drug Absorption and Distribution

 Objectives
1. Define Pharmacokinetics
2. Explain the basic concepts of kinetics- zero order
and 1st order kinetics
3. Explain the biological principles governing drug
absorption, distribution, metabolism and
excretion
4. Define the various pharmacokinetic parameters
5. Demonstrate knowledge of compartmental
pharmacokinetic models;
6. Explain the steady state concept and its value in
dosage design.
 Drug Body Interactions
• The pharmacological effect of a drug
determined by:

– How the body handles the drug

(pharmacokinetics)

– How the drug affects the body

(pharmacodynamics)
 What is Pharmacokinetics (PK)?
• What the body does to the drug
• Fundamental scientific discipline underpinning
applied therapeutics;
• Describes the time course of drug
concentration in compartments of a living
organism;
 Pharmacokinetics
• The scientific study of the rate of drug
movement within biological systems and
the physiological determinants namely
absorption, distribution, metabolism, and
elimination (ADME).
 Distribution

PK PD

What happens to the drug in the body?

 Reaction Rates:
First Order Kinetics
Rate of elimination is proportional to [drug]
[Drug] decreases exponentially w/ time
Plot of C vs. t graph is NOT linear,
decaying exponential. Log C vs. t graph is
linear.
t 1/2 is constant regardless of [drug]
Rate = k C
C = C0 . e (–)kt
First-Order Kinetics
1 Order Log Plot
st
1 Oder Half Life
st
 Reaction Rates:
Zero Order Kinetics
– Rate of elimination is independent of
[drug]
– [drug] decreases linearly with time
– Rate of elimination is constant
– No true t ½
– Rate = k
– C = Co - kt
– C vs. t graph is LINEAR
Zero Order
Comparison of the 1st and zero order

First Order Zero Order

Rate of elimination is Rate of elimination
proportional to [drug] is independent of
[drug] decreases [drug]
exponentially w/ time [drug] decreases
Plot of log [drug] or linearly with time
ln[drug] vs. time are Rate of elimination
linear is constant
t 1/2 is constant No true t ½
regardless of [drug]
 Drug Absorption
Affected by drug characteristics and
physiological factors.

Drug characteristics: Physiological factors:

• Molecular weight, • Route of
• Ionization (pKA), administration,
• solubility, • pH,
• formulation • contents of GI
tract (including
food)
• Blood flow
 Absorption Processes
• Mechanisms of drug transport across
the cell membrane include:
1. Passive Diffusion:
1. Aqueous diffusion
2. Lipid diffusion
2. Special carrier molecules
i. Carrier facilitated diffusion
ii. Active transport processes
3. Vesicular transport:
i. Endocytosis and
ii. Exocytosis
 Passive Diffusion
• Most important absorption process
• Requires conc. gradient
• Not energy dependent
• No carrier proteins required
• Governed by Fick’s law of diffusion:
– Diff. rate (R) = [DAK/h]*[CGI – Cp]
– D is diffusion coefficient, A is surface area, K is lipid water
partition coefficient, h is membrane thickness; CGI – Cp is
difference b/w drug conc. in GIT and plasma
 Active Transport
• Requires carrier protein
• Energy dependent
• Saturable
• Can be competitively inhibited
• Can pump against conc gradient
• E.g. H+ pump, Na/K pump, Ca2+
pump, organic anion transporters
 Carrier Facilitated Diffusion
• Not energy dependent
• Requires a carrier protein
• Favored by conc gradient
• Plays minor role in drug transport
Effect of pH on Drug Absorption
• pH determines the charge on ionizable
drug molecule
• Neutral & lipophilic mols are more readily
absorbed than charged mols
• Weak acids (e.g. aspirin) are better
absorbed at acidic pH
• Weak bases (e.g. pyrimethamine) are
better absorbed at alkaline pH
 Factors Affecting GI Drug
Absorption
• Lipid/water partition coefficient
• Mucosal blood flow
• Surface area of absorption
• GI motility
• Gastric emptying time
• Presence of food
• Formulation of the drug
 Bioavailability (F)
• Fraction of administered dose reaching the
systemic circulation
• Affected by extent of absorption (fg) and
hepatic extraction (1st pass metabolism (fh))
• F = f g X fh
• IV admin = 100 %; most other routes <100 %
Effects of Absorption Rate on
Plasma Concentration
 Distribution
• Membrane permeability
– Drugs cross membranes to reach site of action
• Plasma protein binding
– bound drugs do not cross membranes
• malnutrition = albumin =  free drug
• Lipophilicity of drug
– Lipophilic drugs easily cross the membranes
– lipophilic drugs accumulate in adipose tissue
• Volume of distribution
 Factors Affecting Drug
Distribution
1. Blood Flow:
• Highly perfused organs receive more
drugs than poorly perfused organs
• Liver, kidney, and brain are highly
perfused
• Skin, bones, and skeletal muscles are
poorly perfused
 Factors Affecting Distribution
2. Membrane permeability:
• Capillary structures differ in different organs
with respect to the size of slit junctions;
• Liver and spleen have large slit junctions
• Brain tissue has no slit junctions rather tight
junctions
• Nature of the drug molecule also affects
permeability
 Protein and Tissue Binding
3. Plasma Protein Binding:
• Bound drug is inactive
• Only free fraction is active
• Albumin and α-1acid glycoprotein are
major binding proteins
• Displacement of bound drug can lead to
significant drug-drug interactions
 Protein and Tissue Binding
Tissue Binding:
• Drugs can bind to tissue components –
proteins, lipids, and nucleic acids
• Binding can lead to drug accumulation in
the tissue
– Accumulation of cyclophosphamide in renal
tissues is responsible for its renal toxicity
 VOLUME OF DISTRIBUTION
Vd: apparent volume of the body in which the
drug uniformly distributes to form a
homogenous solution with the same
concentration as in plasma

Total amount of drug that entered the body

(mg) divided by the concentration of drug in
plasma (mg/dl)
 Vd = amount of drug in body (D) ÷ plasma conc (Cp)

Useful for calculating loading dose

 Body Fluid Compartments
• Plasma water: 6 % of body weight or 4.2 L
– Highly protein bound drugs distribute mainly in
this compartment e.g., heparin
• ECF (plasma + interstitial fluid) – 20 % BW
or 14 L
– Drugs that permeate the capillaries but do not
permeate the cell membrane distribute in this
phase e.g., aminoglycosides
 Body Fluid Compartments
• Total Body Water – 60 % BW or 42 L
– Ethanol distributes freely in the total body
water
• Effect of Vd on t½:
– Large Vd means most drugs outside plasma
– Increased Vd leads to increase t½ leads to
increased duration of drug action
 Barriers to drug distribution
• Blood-brain barrier
• Only permeable to lipophilic drugs
• Fetoplacental unit:
• Permeable to both lipophilic and hydrophilic drugs
• Enzymes can metabolize drugs
• Special transporters act as efflux pumps e.g. p-
glycoprotein

• Blood-testis (Sertoli Cell) Barrier – prevents

toxic chemicals from affecting the developing
cells in the seminiferous tubules
 Pharmacokinetic
Compartments
• PK compartment is a region of tissue or fluid
through which a drug can diffuse and equilibrate
with ease

• Each compartment is usually separated by a

barrier form adjacent compartment

• Drug flow and distribution between

compartments takes more time than within an
compartment
 Compartmental Models:
Single bolus administration
• One compartment model:
• Drug distributes uniformly in the body as if it
were a single compartment
• Two compartment models:
• Drug distributes into a central compartment
(plasma) and from here redistributes into the
peripheral compartment
Effects of Absorption &
Elimination Rates
• Rapid absorption will increase peak plasma conc
• Rapid absorption decreases time of onset of
drug effect
• Rapid absorption decreases duration of effect
• Rapid elimination will decrease peak plasma
conc
• Rapid elimination decrease duration of drug
effect
Multiple Dosing: IV Injections
• If doses are
given after long
intervals
compared to the
t ½ of the drug,
the previous
plasma conc
would come to
zero before the
next dose:
Multiple Dosing: IV Injections
• If the dosing intervals
are shorter however,
a fraction of the drug
will still be in plasma
and subsequent
doses will lead to
ACCUMULATION of
the drug.
Multiple Dosing: IV Injections
• If the drug is
given every
t1/2, a steady
state will be
achieved after
4-5 t½s as
shown.
Multiple dosing model
Continuous Infusion Model
Steady State Concept
 Steady State Concept
• Steady State: The amount of drug
administered is equal to the amount of
drug eliminated within one dosing interval
resulting in a plateau or constant serum
drug level
• Drugs with short half-life reach steady
state rapidly; drugs with long half-life take
days to weeks to reach steady state
 Steady State
• Attained after 4-5 t ½
• Dosing rate = elimination rate
• Actual plasma conc. oscillates between
peak (Cmax) and through (Cmin) values with
midpoint at Css
• Therapeutic objective to keep Cmax below
MTC and Cmin above MEC