Pharmacokinetics 1:

Administration & Absorption

A/Professor Ken Rodgers
School Of Life Sciences
Department of Health Sciences

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 Learning objectives

u Understand the effect of pH partitioning

and lipid solubility on drug absorption
u Describe factors affecting the absorption
of drugs via oral administration especially
first-pass metabolism
u Understand the suitability, limitations and
precautions of various routes of
administration
u Outline the concept of bioavailability

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 Reference

u Rang and Dale’s Pharmacology, 9th Edition,

Churchill Livingstone, Sydney by Rang HP,
Dale MM, Ritter JM, Flower RJ, Henderson, G
(2019)
u Absorption and distribution of drugs– Chapter 9

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 Absorption
u Low lipid solubility – poorly
absorbed from gut (eg
tubocurarine)

u Very small molecules

(aquaporins form a pore)

u Absorbed by carrier-mediated
(pump) transfer (eg
levodopa, fluorouracil)

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Passage of drugs across membranes

u Cell membranes form barriers

between aqueous compartments in
the body

u Cell membrane are relatively

impermeable to ionised drugs junctions

u Special carriers and endo/exocytosis

are probably not very important in drug
absorption (few exceptions) junctions

u Main process is probably pH

partitioning

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 pH Partitioning 1

u Most drugs, or their salts, are weak

acids/bases

u Thus the proportion of ionised to non-

ionised drug depends upon the pH

u Ionised drugs are not very lipid soluble -

only non-ionised form of drug crosses
membrane readily

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 pH Partitioning 2
u Biological fluids (blood, stomach
and intestinal contents, urine) have
different pH values
Stomach Intestine

u Can affect how and where drug is pH = 2-3

absorbed and distributed and how
well it is excreted

u For weak acids and weak bases %

ionisation is determined by the
Henderson-Hasselbalch equation
pH = 5-6
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 pH Partitioning 3a
HCl (strong acid)
exists as H+ + Cl-
no charge
Ka lipid soluble
u Weak acid AH A- + H+
charged
(Ka – dissociation constant) water soluble
If pH = pKa
=0
u pH = pKa + log10 [A-]/[AH]
[A-]/[AH] = 1
Ka 50%:50%

u Weak base BH+ B + H+

no
charge
u pH = pKa + log10 [B]/[BH+] lipid
soluble

u Ionised = unionised if pH = pKa

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 pH Partitioning 3
u Degree of ionization is determined by the pKa of drug and
pH of the solution
u pKa is the pH of the aqueous solution in which the
compound is 50% ionised and 50% non-ionised.
u For acids:
u pKa – pH = log ( [non-ionised] / [ionised] )
u For bases:
u pKa – pH = log ( [ionised] / [non-ionised] )
u Thus
u [HA] / [A–] = 10(pKa – pH ) or
u [BH+] / [B] = 10(pKa – pH )

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 pH=pKa

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 pH Partitioning 4

u Eg. aspirin (weak acid), pKa = 3.5

pH 1.5
100%
un-ionised
pKa
3.5

pH 5.5
100%
ionised

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 pH Partitioning 5
u Eg. pethidine (weak base), pKa = 8.6

pH 6.6
100% ionised

pKa
8.6

pH 10.6
100% un-ionised
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 ~50:50

~50:50

Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between urine, plasma and gastric
juice according to their pH differences. Numbers represent relative concentrations (total plasma concentration
= 100). It is assumed that the uncharged species in each case can permeate membranes separating the
compartments, and therefore reaches the same concentration in all three. Variations in the fractional ionisation
as a function of pH give rise to the large total concentration differences with respect to plasma.
 pH Partitioning 6
u Weak acids (with pKa >3)
preferentially absorbed
u Weak bases (with pKa <7)
Absorption of drugs
preferentially absorbed from intestine (pH 5)

pKa =11 so
will be ~100%
ionised in ph5
pKa =1 so will be ~100%
ionised in ph5

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 Applications of pH Partitioning 1
u Alkalinisation of urine (NaHCO3): increases rate of
excretion of weak acids (more ionised) eg phenobarbital
(pKa = 7.4)

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 Applications of pH Partitioning 2
u Acidification of urine (NH4Cl): increases rate of
excretion of weak bases (more ionised). Eg.
Chlorpromazine pKa 9.3

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Applications of pH Partitioning 3
u Increasing plasma pH (NaHCO3): will shift weakly
acidic drugs from the CNS to plasma (more ionised)

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 Summary: cellular barriers
ü To traverse cellular barriers (e.g. gastrointestinal
mucosa, renal tubule, blood-brain barrier,
placenta), drugs have to cross lipid membranes.

ü Drugs cross lipid membranes mainly by (a)

passive diffusion

ü The main factor that determines the rate of

passive diffusion across membranes is a drug's
lipid solubility (pH partitioning). Molecular weight
is less important.
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 Summary: pH partitioning
ü Many drugs are weak acids or weak bases; their state of
ionisation varies with pH according to the Henderson-
Hasselbalch equation.
ü Only the uncharged species (the protonated form for a
weak acid, the unprotonated form for a weak base) can
diffuse across lipid membranes; this gives rise to pH
partition.
ü Weak acids tend to accumulate in compartments of
relatively high pH (highly ionised)
ü Weak bases tend to accumulate in compartments of
relatively low pH (highly ionised).
ü When the pH = Pka the weak acid/base is 50% ionised

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 The oral route of drug administration
u Oral route (enteral), p.o.
(per os)
u 1. most common route
u 2. usually safest
u 3. most convenient
u 4. most economical

u Surface area, not pH

partition, is main determinant
of site of absorption –
villi/microvilli in small intestine
> stomach

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 Rapid oral absorption
u So for rapid drug absorption, typically …
u Take tablet with a large glass of water (eg 200
mL)
u Take on an empty stomach eg at least half an
hour before food (as long as gastric irritation is
not a problem)

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 First-pass metabolism

u Difficulties with oral route 1

u 1. First-pass metabolism
u Before entering the systemic circulation, blood leaving the GI
tract passes through the liver
u Thus, drugs that are highly metabolised by the liver may attain
very low circulating levels relative to those attained after
parenteral administration

Must Drugs undergoing substantial first-pass metabolism Oral dose

dissolve Aspirin Metoprolol is higher
under Glyceryl trinitrate Morphine than
tongue Isosorbide dinitrate Propranolol parenteral
Levodopa Salbutamol dose
Lignocaine Verapamil
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First-pass metabolism

Drugs taken orally are

absorbed in stomach and
small intestine.

Blood vessels take the drug

directly to the liver.
Liver
Drug passes through liver
before being distributed round
the body

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 Irregular absorption

u Difficulties with oral route 2

u 2. Irregular absorption depends on stomach
contents
u delayed gastric emptying time
u altered stomach pH due to food

u decreased splanchnic blood flow in Heart Failure

u complex formation of drug with food products (eg

tetracyclines with milk)

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 Absorption of alcohol

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 Difficulties with oral route 3
u 3. Gastrointestinal irritation eg aspirin
u 4. Low pH may inactivate certain drugs eg penicillins, insulin
u 5. Particle size (small = more rapid absorption)
u (eg see digoxin graph)
u 6. Requires patient compliance

Decreasing particle size

increases absorption

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 Oral bioavailability
u All the above factors influence oral bioavailability

u Fraction of orally administered drug that reaches the

systemic circulation

u Two drugs with identical chemical composition that yield

different blood concentrations and different effectiveness,
differ in bioavailability (and are not bioequivalent)

u Varies between individuals

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 Overview of bioavailability
u eg bioavailability of morphine via oral
administration is only 20-33% when compared
to IV administration

u Intravenous 100% by definition

u Intramuscular 75 to <100%
u Subcutaneous 75 to <100%
u Oral 5 to <100%
u Rectal 30 to <100%
u Inhalation 5 to <100%
u Transdermal 80 to <100%
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 Sublingual (SL)

u Under the tongue

u Rapid absorption

eg. glyceryl trinitrate

u Avoids exposure of drug to
gastric pH
u Avoids first-pass metabolism
u Taste could be an issue

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 Intravenous
u Absorption pattern
u Precise, accurate and potentially immediate effects (absorption
phase is bypassed)
u Suitable for large volumes and mixtures

u Special Utility
u Valuable for emergency use, permits titration of dose
u Usually required for high molecular weight protein and peptide
drugs (eg. tPA)
u Limitations and precautions
u Greater risk of adverse effects
u High concentration attained rapidly
u Risk of embolism
u Must inject solutions slowly as a rule
u Not suitable for oily solutions or poorly soluble drugs

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 IM and subcutaneous injection
u Absorption pattern
u Prompt absorption from aqueous solution, but slow and
sustained from repository preparations
u Suitable for:
u Poorly soluble suspensions and slow release implants (sc)
u Moderate volumes and some irritating substances (im)

u Appropriate for self-administration (eg insulin)

u Limitations and precautions

u Not suitable for large volumes and pain and necrosis at
injection sites for certain drugs (sc) eg thiopentone
u Precluded during anticoagulant therapy (im)

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 Rectal (PR)
u Can be used for a local or
systemic effect
u Unconscious patients, children
with poor IV access, if patient is
vomiting
u Easy to terminate exposure
u Absorption may be variable

u Good for drugs affecting the

bowel such as laxatives /
cathartics / drugs for ulcerative
colitis
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 Spinal / Epidural
u Into spinal/epidural space for delivery of local
anaesthetics/opioids for pain control

u Preferred over GA in lower abdominal or lower

limb surgery or in child birth

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 Topical (TOP) 1
u Mucosal membranes
u Nasal, vaginal, etc.
u zolmitriptan spray - migraine

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 Topical (TOP) 2
u Skin
u 1. dermal (local)
u 2. transdermal (systemic)
u Stable blood levels
u No first pass metabolism
u Drug must be potent and
lipophilic
u scopolamine – motion
sickness
u oestradiol – hormone
replacement
u fentanyl – pain
u clonidine – hypertension
u nicotine – tobacco withdrawal
u nitrates – angina

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