The document discusses pharmacokinetics, focusing on the absorption, distribution, metabolism, and excretion (ADME) of drugs. It highlights various routes of administration, factors affecting drug permeation and distribution, and the metabolism processes that occur mainly in the liver. The text also covers the concepts of clearance and half-life, which are crucial for designing effective drug dosages and understanding the drug's therapeutic effects.

1. Pharmacokinetic Principles

2. Pharmacokinetics
 Pharmacokinetics is essentially the study of the
absorption, distribution, metabolism and excretion
(ADME) of drugs

3. Absorption
Is the transportation of the drug from the
site of administration to the general
circulation
Drug absorption depends on:
1) The route of drug administration
2) The anatomy and physiology of the
absorption site

4. Route of Drug Administration
 Oral (enteral):
– GIT absorption means that the drug is transported via the portal
system to the liver and undergoes first pass metabolism
– First pass metabolism may render some of the drug inactive
Systemic
circulation
Oral
Stomach
Duodenum
Liver
Portal
circulation

6. Route of Drug Administration
 Mucous membranes: highly vascular which allows rapid entry of the
drug to the systemic circulation. This route avoids first pass
metabolism and the hostile gut environment. It includes sublingual,
ocular, lung, intranasal, rectal, vaginal and more.
 Injection (parenteral) of drugs directly into tissue : avoids first pass
metabolism and provides rapid delivery to the site of action. It
includes; IV, IA, IM, SC, intraperitoneal (IP) and intrathecal (IT)
 Transdermal and percutaneous administration: passive diffusion of
highly lipophilic drugs across the skin. This approach provides slow
onset of action and potential for slow, continuous drug delivery (e.g.
nicotine patches).

7. Bioavailability (F)
• The fraction of unchanged drug reaching the
systemic circulation following administration by
any route
• Since IV injection transfer the drug directly into the
general circulation, it provides 100% bioavailability

8. 0 1 2 3 4 5 6 7 8 9
0
10
20
30
40
50
60
70
80
Plasma
concentration
Time (hours)
IV route
Oral route
Bioavailability
=
(
AUC
)
iv
(
AUC
)
o
×
100

9. The movement of drugs in the body: permeation
 For a drug to produce effect at the site of action, it
should be able to cross/ translocate/ penetrate through
the various barriers/ membrans between the site of
administration to the site of action

10. Permeation
There are two main ways by which drug molecules cross through the various
barriers:
1. Passive diffusion governed by Fick’s law
• Describes the passive flux of molecules down a concentration gradient
Rate= (C1 – C2) xArea x Permeability coefficient
Thickness
Where C1 is the higher conc.; C2 is the lower conc.,area is the area across which
the diffusion is occurring. In the case of lipid diffusion, the lipid:aqueous
partition coefficient is a major determinant of mobility of the drug
2. Carrier-mediated membrane transport: facilitated and active

11. Ionization of weak acids and weak bases
• Many drugs are weak acids or bases that are present in solution as
both the non-ionized and ionized species
• Nonionized molecules are usually lipid soluble and can diffuse
across membrane
• The transmembrane distribution of a weak electrolyte is
influenced by its pKa and the pH gradient across the membrane
• The relationship of pKa* and the ratio of acid-base concentration
to pH is expressed by the Henderson-Hasselbalch Equation

12. Henderson-Hasselbalch Equation
For weak acids
pH = pKa + log10 [nonprotonated species]
pH = pKa + log10 [A-
]
[
HA
]
pH = pKa + log10 [B]
[
BH
+
]
For weak bases
[protonated species]

13. pH of the medium
100%
50%
0%
1
75%
25%
Role of pH in ionization of a Weak base
%
of
Unionized
form
14

14. pH Effect: Acid/Base effect on absorption
Weak acids would be
absorbed under acidic
conditions (e.g. stomach).
Weak bases would be
absorbed at neutral pH (e.g.
intestine, nasal passage).
pH
i.e. pH ~2 stomach
pH
i.e. pH ~7.4 intestine,
nasal passage

15.  Manipulating the pH of the urine to increase the ionized form
of the drug in the lumen may be used to minimize the amount
of reabsorption, and hence increase the excretion of an
undesirable drug (alkalinization for weak acids &
acidification of the weak basis)

17. Distribution
 It the process by which a drug reversibly leaves
the blood and enters the interstitium
(extracellular fluid) and/ or the cells of the
tissues
 Primarily depends on:
 Regional blood flow
 Capillary permeability
 Binding to plasma proteins
 Chemical nature of the drug

18. Volume of distribution (Vd)
 A hypothetical volume that represents the distribution of the
drug between plasma and tissue compartments
 It relates the amount of drug in the body to the concentration of
drug (Cp) in blood or plasma:
 Most of the time the volume of distribution does not actually
equal the real volume of the compartments; it is simply a
model to help understand drug behavior
 Volume of distribution is influenced by body composition,
physiologic process, and the chemical and physical properties of the
drug
Vd
= A
Cp

19. Volume of distribution (Vd)
 Drugs confined to the plasma compartment (plasma volume 0.05 L/kg BWT) (e.g. heparin and
warfarin): very large molecular weight, low lipid solubility, or binds extensively to plasma proteins
 Drugs distributed in the extracellular compartment (intracellular volume 0.2 L/kg) (e.g.
aminoglycoside antibiotics): low molecular weight and hydrophilic
 Drug distributed throughout the body water (total body water 0.55 L/kg): lipid-soluble drugs that
readily cross membrane
 Drugs that are extremely lipid soluble (e.g. thiopental) may have unusually high volume of
distribution)
 Other sites: Milk, bone, muscles
Try This______
 3.5 L/ 70 Kg--------What body compartment?
 14 L/ 70 Kg--------What body compartment?
 5.5 L/ 70 Kg -------What body compartment?

20. Protein binding
• Many drugs circulate in the bloodstream bound to plasma
proteins
• Albumin is a major carrier for acidic drugs and α1-acid
glycoprotein (AAG) binds basic drugs
• The binding is usually reversible
• Binding of a drug to plasma proteins limits its
concentration in tissues and at its site of action because
only unbound drug is in equilibrium across membranes

21. Metabolism
• Involves enzymic conversion of one chemical entity
to another within the body
• The liver is the major site for drug metabolism
• Specific drugs may undergo biotransformation in
other tissues, such as the kidney and the intestine

22. Metabolism
• The enzyme systems for drug metabolic
biotransformation reactions can be
grouped into two categories:
1) Phase I oxidative or reductive enzymes
2) Phase II conjugative enzymes

23. Drug metabolism: Liver
Kidney
Urine
Drug molecule
More hydrophilic
metabolite
Conjugate
Bile
Feces
De-conjugation
and reuptake
(
entero-hepatic
cycling
)
Intestines
I
II

24. Phase I reactions
• Usually convert the parent drug to a more polar
metabolite by introducing a functional group (-OH, -
NH2, -SH)
• Phase I metabolism may increase, decrease, activate
(prodrug, e.g. enalapril) or leave unaltered the
drug’s pharmacologic activity
• Phase I reactions are catalyzed by the cytochrome
P450 (CYP450) system

25. Phase I reactions
• CYP450 is composed of many families of
isoenzymes known as isoforms
• Six isoforms are responsible for the vast majority
of CYP450-catalyzed reactions: CYP3A4, CYP2D6,
CYP2C9/10, CYP2C19, CYP2E1, and CYP1A2
• Variability in the activity of CYP450 enzymes is
linked to a range of factors including genetic,
environmental, and developmental

26. Relative Amounts of Individual Human Hepatic CYPs
Shimada et al., JPET: 1994
Other
26%
CYP3A4
30%
CYP1A2
13%
CYP2E1
7%
CYP2A6
4%
CYP2B6
<
1%
CYP2C
18%
CYP2D6
2%
CYP2C9
13.6%
CYP2C19
2.7%
CYP2C8
1.7%
Lasker et al., Arch. Bioch. Biophys:1998

27. Phase II reactions
• Lead to the formation of a covalent linkage between
a functional group on the parent compound or phase I
metabolite and endogenously derived glucuronic
acid, sulfate, glutathione, amino acids, or acetate
• The highly polar conjugates generally are inactive and
are excreted rapidly in the urine and feces
• Neonates are deficient in this conjugation system,
making them particularly vulnerable to drugs such as
cholamphenicol (gray baby syndrome)

28. Renal excretion
Three fundamental processes account for renal drug
excretion:
Glomerular filtration:
Depends on glomerular filtration rate (GFR) and the
extent of plasma binding of the drug , and molecular
weight of the drug. Lipid solubility & pH do not
influence the passage of drugs into the glomerular
filtrate
Active tubular secretion
Passive tubular reabsorption

29. Clearance (CL)
• The main PK parameter describing elimination
• It is the most important concept to consider when designing a
rational regimen for long-term drug administration
(Maintenance dose)
• Defined as the volume of plasma/fluid that is cleared of drug
that is removed from the body in unit time
Eliminating
Organ
Kidney, liver, etc.
Conc in Conc out
Conc
eliminated

30. Clearance (CL)
• Total body (systemic) clearance ,Cltotal, is the sum of
the clearance from various drug metabolizing (mainly
the liver) and drug excreting organs (mainly the
kidney) [Additive process]:
CLtotal = CLhepatic + Clrenal + CLpulmonary + Clother
• Units of clearance are volume/time (e.g. L/h or
ml/min)

31. Clearance (CL)
Drug clearance depends on:
1) Extraction ratio: a measure of the efficiency
with which an organ of elimination can remove
the drug from the blood
2) Blood flow rate: the rate of drug delivery to the
eliminating organ
Clearance = Flow × Extraction ratio

32. High Extraction Drugs (>0.7): Flow-dependent elimination
• Examples: morphine, pethidine, propranolol, verapamil
• Blood flow to the organ is the main determinant of
drug delivery
• Drugs with high extraction ratio have a low oral
bioavailability due to extensive metabolism on first
pass through the liver

33. Low Extraction Drugs (<0.3): Capacity limited elimination
• Examples: amoxicillin, digoxin, diazepam, prednisolone,
warfarin
• Drug is poor substrate for the elimination process
• Clearance depends on plasma protein binding
• They are particular susceptible to drug-drug interactions

34. Half-Life (t1/2)
 It is the time required for the plasma concentration or
the amount of drug in the body to change by one-half
(i.e. 50%)
 The half-life is a derived parameter that changes as a
function of both CL and Vd:
t1/2
=
0.693
×
Vd
CL

35. Drug Concentration
Time
C1
1/2C1
t1 t2
t1/2
t1/2
=
0.693
×
Vd
CL

36. 100
187.
5
194
175
150
75
87.
5
94 97
50
200
100
…
…
Accumulation to Steady State 100 mg given every half-life
Knowledge about half-life is useful in determining the time to
reach/attain steady state (ss) or to decay from steady state conditions
4-5
half lives to reach steady state

37. Rational dosage design
 Is based on the assumption that there is a target
concentration that will produce the desired
therapeutic effect
 By considering drug’s PKs, it is possible to
individualize the dose regimen to achieve the target
concentration

38. Loading dose
 Is one or a series of doses that may be given at the onset of therapy
with the aim of achieving the target concentration rapidly
 A loading dose may be desirable if the time required to attain steady
state by the administration of drug at a constant rate (four elimination
half-lives) is long relative to the temporal demands of the condition
being treated
 The appropriate magnitude for the loading dose is:
Loading dose = TC × Vd

39. Maintenance dose
• In most clinical situations, drugs are
administered in a series of repetitive doses or
as a continuous infusion to maintain a steady-
state concentration of drug associated with the
therapeutic window
• Just enough drug is given in each dose to
replace the drug eliminated since the preceding
dose:
Rate in = Rate out

40. Maintenance dose
• Clearance is the most important pharmacokinetic
term to be considered in defining a rational steady
state drug dosage regimen:
CL= clearance; TC= target concentration
Maintenance dose = CL × TC

41. 0 5 10 15 20 25 30
0
1
2
3
4
5
6
7
Time
plasma
concentration
Toxicity
Effective
Repeated
doses –
Maintenance
dose
Loading
dose