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Year Level 6 [Module 2: General Concepts of Disease and Therapeutics]
PRINCIPLES OF PHARMACOKINETICS (1)
Marcelo Imasa, MD | [Pharmacology]
OUTLINE:
I. INTRODUCTION
A. DEFINITION
B. PROCESSES
II. LIBERATION
A. MODIFIED RELEASE VS. IMMEDIATE
RELEASE DRUG PRODUCTS
B. POTENCY AND POTENTIATION
III. TRANSPORT PROCESSES
A. PASSIVE TRANSPORT
B. CARRIER-MEDIATED TRANSPORT
C. CONVECTIVE TRANSPORT
D. PINOCYTOSIS
IV. ABSORPTION
A. DEFINITIONS
B. BIOAVAILABILITY
C. BIOEQUIVALENCE
D. FACTORS AFFECTING ABSORPTION
I.
II.
July 8, 2009
o
o
A.
May also be non-intentional – poor quality
drug products (ex. Cloxacillin – highly
hygroscopic that if not properly formulated,
it liquefies during storage then eventually
solidifies that the drug will no longer be
absorbed)
If intentional, it is called modified-release
product (ER = extended release, SR =
sustained release)
Modified Release vs. Immediate Release drug products

Compared using drug plasma concentration vs time
graph

Get volunteers to take drugs, then measure the levels
in the plasma (y-axis) as function of time (x-axis)
Graph 1. Plasma Concentration of Drug vs Time
INTRODUCTION

Pharmacokinetics – what the body does to the drug

Includes the processes the drug undergoes as it
reaches the biological site of action and leaves the
body

LADMER system
o Liberation
o (Transport)
o Absorption
o Distribution
o Metabolism
o Excretion

Elimination is the general process to refer to both
metabolism and excretion
LIBERATION

Drugs are usually NOT in pure form

Drug product = drug (active) + excipients (substances
added to produce a form that can be delivered to the
patient)

Liberation – is the process of release of the drug from
the drug product

Objective of liberation: to make the drug available in
an aqueous solution form
o Why?
o Practically all the transport processes
require that the substance be in aqueous
solution form

Exceptions among the drug products taken P.O.:
syrups, elixirs – active ingredients are already in
aqueous solution
(Note: PO means per orem or taken orally and
swallowed

Liberation is a highly modifiable process
o You can change how the drug is released
from the drug product
o May be intentional - designed by whoever
formulated the drug
Where:
MEC (minimum effective concentration) - the smallest
concentration of the drug in the blood that produces a
response or effect
MTC (minimum toxic concentration) – the upper range of
the therapeutic range; the minimum concentration that
can produce toxicity to the body
Therapeutic Range – area between MTC and MEC
Onset – time when concentration reaches MEC
Offset – time when concentration goes below MEC
Duration of Action – interval between Onset and Offset of
drug action; effectivity time

Aim of manufacturers: drug concentration in the
blood reaches the MEC without reaching the MTC

With modified release:
o The concentration of the drug between the
ONSET and OFFSET reaches a plateau
instead of a peak thus there is less
likelihood of reaching the MTC compared to
immediate release (Example: with
immediate release, an anti-diabetic drug
can reach MTC easily and cause
hypoglycemia. With modified release, the
incidence of hypoglycemia is decreased)
Team 7 | Agustin, Aranjuez, Magat, Maglaque, Ocampo, Parco, Regalado, Serrano, Tan, Tanbonliong
PRINCIPLS OF PHARMACOKINETICS (1)
Year Level 6 [Module 2: General Concepts of Disease and Therapeutics] July 8, 2009
o There can be a delay in the onset of action
environment of the stomach, the weak acid
but longer duration of action
drug will undergo higher rates of passive
transport assuming all other factors to be

Immediate release = usually how drugs are
equal
discovered (no modifications done)
o In an acidic environment, with a weak base

It is mandatory that the pattern of release, if it is
drug, the reaction will also shift to the left,
modified, is put in drug labels
towards the ionized form of the base (BH+).
o XR = extended release, SR = sustained
This lowers the rate of transport of the
release, PR = Prolonged-release, etc
weakly basic drug in the stomach.
B. Potency and Potentiation
o Conversely, in a basic environment, the

Different from patterns of release
non-ionized form of the weakly basic drug

Potency - dose that produces 50% of maximum effect
(B) is favored, resulting to high transport

Potentiation – making the drug “more potent”; done
rates of the drug in the small intestines
by lowering the dose needed to achieve the same

In
short,
weak
acids are optimally absorbed in the
maximum effect
stomach and weak bases are optimally absorbed in
the small intestines (assuming all other factors are
III. TRANSPORT PROCESSES
equal)
B.
Carrier-mediated
Transport
E. Passive Transport

A
number
of
drugs
in the market requires carriers

movement along a concentration gradient; NOT

Carriers
are
proteins
with specific binding sites and
energy-requiring; SLOW but DOMINANT transport
will undergo conformational change when bound
process
which enables movement of the drug inside the cell

Requirements for drugs to undergo passive transport

Types
o Small (MW<400-600)
o Active transport – requires energy, movement is
o
Lipophilic – lipid-soluble (since the plasma
against the electrochemical gradient
membrane consists of lipids)
Ex. Na+/K+ ATPase

Governing principle: Fick’s law of diffusion – rate of
o
Facilitated diffusion – no energy input,
transport is directly proportional to the surface area,
movement is down the electrochemical gradient
diffusion coefficient and concentration gradient and
Ex. GLUT4 – insulin-sensitive glucose transporter
inversely proportional to the thickness of the
for the permeation of glucose across a muscle
membrane
cell membrane

Common features
1. Selectivity/specificity
2. Subject to competition/ inhibition/ antagonism
Where
Ex. Isoniazid (anti-TB drug) is associated with a
A= surface area
side-effect – peripheral neuropathy, which can
(C1 – C2)=concentration gradient/difference
be resolved by Vitamin B6. They have similarity
h=thickness of membrane
in structure that use the same carrier. Problem is
d = diffusion coefficient – lipophilicity of drug
that Isoniazid and VitB6 are formulated together
 depends on (1) degree of ionization – many
and are taken at the same time. Isoniazid can
drugs are weak acids/bases.
block VitB6 or vice versa. This reduces the
o Note that the non-ionized form will pass the
efficacy of the drug. This can be solved through
membrane. Ionized forms will have less
timing. Advise the patient to take isoniazid in the
diffusion coefficient, thus lesser degree of
morning and Vit B6 in the evening.
transport.
3. Saturability – based on a limited number of
o For a weak acid:
carriers; even if you give higher doses of the
The lower the Ka (dissociation
drug, the rate of transport will remain the same
constant) or higher the pKa (where pKa
o First-order kinetics – rate of transport
=-log Ka) the faster is the rate of
increases as you increase the dose
passive transport
o Zero – order kinetics – rate of transport
o For a weak base:
remains the same even if you increase the
The higher the Ka or the lower the pKa,
concentration
the faster is the rate of passive
o When a drug at low concentration behaves
transport
at first-order kinetics, and at high
 Also depends on partition coefficient (lipid-H2O)
concentration behaves at zero-order

The dissociation of a weak acid or weak base is
kinetics, this is called capacity-limited
guided by the Le Chatelier’s Principle:
kinetics/ saturable kinetics/MichaelisWeak acid:
Menten kinetics – this is characteristic of
ALL CARRIER-MEDIATED processes
Weak Base:
o
Team 7
In an acidic environment, with a weak acid,
the reaction will shift to the left, towards its
non-ionized form (HA). In the acidic
C.
Convective Transport

Transport across pores/channels

important for movement of small ions (K+, Na+, etc.)
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PRINCIPLS OF PHARMACOKINETICS (1)
Year Level 6 [Module 2: General Concepts of Disease and Therapeutics] July 8, 2009
Graph 3. Bioequivalence
D.
Pinocytosis

Vesicle-mediated, energy requiring transport

Exception to the rule that the drug must be in
aqueous form

Drugs that undergo pinocytosis are LARGE LIPIDS

The drug must be in the form of MICELLES – lipid
globule stabilized by surfactants (surface-active
agents i.e., bile salts in the small intestines)

Examples: large lipids, fat-soluble vitamins (ADEK)
IV. ABSORPTION
A.
B.
Definitions

Physiologic definition: rate and extent of
disappearance of the drug from the site of
administration (or from the site it was administered)
Ex. PO (per orem) drug – physiologically absorbed in
the gastrointestinal mucosa (entering the portal
circulation)

Pharmacologic definition: rate and extent of drug
entry into the SYSTEMIC CIRCULATION (circulation
AFTER the liver; AFTER the portal circulation)
o test: extract blood from the peripheral vein
and detect the drug in the sample
Bioavailability

measure of the RATE and EXTENT of drug entry into
the systemic circulation

Bioavailability studies – subjects are healthy people of
same age and weight

Bioavailability graph – differs according to whether
drug is given intravenously or extravascularly
Graph 2. Bioavailability of a Drug
Where
Cmax- measures both rate and extent – most variable
parameter
Tmax – measures the rate (how fast the drug is absorbed)
AUC – measures extent (how much of the drug is
absorbed) – most important parameter (i.e., for BFAD)
Note: these three parameters are subject to intra- and
inter-individual variability
C.
Bioequivalence

a measure of the similarity in the bioavailabilities of
generic and the innovator drug product
Team 7





D.
Ratio is computed for the three parameters (Cmax,
Tmax, AUC)
The denominator is always the standard (innovator
drug)
Two drugs are bioequivalent if the ratio is between
0.8 and 1.25.
Bioequivalent studies are only conducted on drugs
with bioavailability problems.
If the drug is administered directly into the systemic
circulation, it is expected, by definition, to have 100%
bioavailability
Factors affecting Absorption
o Dose size administered – the bigger the dose, the
higher the absorption (greater rate and absorption)
o Ex. Biogesic- 500 mg paracetamol vs Tylenol
650 mg – it is expected that Tylenol would
have greater rate and extent of absorption
o Surface area of absorption – explains why inhalational
drugs have very high absorption rates and extents
(lungs have very large surface areas)
o Ex. Stomach vs small intestine (SI) – most
drugs will be absorbed in the SI because of
the villi and microvilli (even for weak acids,
surface area of SI is much greater than that
of the stomach)
o Exceptions: aspirin, ethanol - highly
absorbed in the stomach

Degree of perfusion of the absorption site
o Ex. Stomach (pancreaticoduodenal artery)
vs small intestines (arcuate arteries – more
perfused)
o this is also another explanation for the high
absorption in the lungs (alveolar capillaries
are abundant)
o a MODIFIABLE factor
o Lidocaine – local anesthetic for minor
operations, can cause problems if
systemically absorbed (can cause cardiac
arrhythmias)
Solution: give lidocaine with epinephrine (a
vasoconstrictor) - the blood vessels will
constrict, minimizing the systemic
absorption of lidocaine
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PRINCIPLS OF PHARMACOKINETICS (1)

Year Level 6 [Module 2: General Concepts of Disease and Therapeutics] July 8, 2009
o For topical steroids, make sure you instruct
the patient not to rub the skin since this will
dilate the vessels and cause the drug to
enter systemic circulation
Gastric emptying time (GET) – important for drugs
given per orem (PO) or swallowed drugs
o The time it takes for the stomach to empty
all of its contents (2-3 hours)
o The stomach is a poor absorbing
environment because of
1. a small surface area
2. low degree of perfusion
3. lined by thick mucus
o Factors that increase GET and delay rate of
absorption
1. Hot food, high-protein food, high-fat
food
2. Stress, heavy exercise
3. Gastric ulcer
4. Lying on the left side (due to position
of the stomach)
5. Anti-motility drugs i.e., opioids
(imolium, loperamide), anticholinergic
drugs
o Factors that decrease GET and increase rate
of absorption
1. Cold food
2. Mild exercise
3. Gastrectomy
4. Diabetes Mellitus
5. Lying on the right side
6. Motility enhancers i.e.,
Metoclopromide (Plasyl),
Domperidone (Motilium)
FORMAL SPACE FILLERS HO! Bigger resolutions of graphs para
sa mga nearsighted:
Team 7
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