Drug Absorption

Dr Omar Janneh
ojanneh@[Link]

Jenner Wing, First Floor,

Corridor 4, Room 1.118
T: 0208 725 5614
 Learning outcomes
• Define ADME and describe its importance
• Describe factors that affect the absorption of drugs, e.g. enterohepatic
recirculation and first pass effect
• Briefly describe the Lipinski’s rule of 5: the simplistic guide to the complicated
business of designing orally bioavailable drugs
• Define ion trapping
• Define the Henderson-Hasselbach equation with reference to the absorption
of aspirin
• Describe the effect of pH on the absorption (and excretion) of aspirin
 ADME
Absorption: Process by which the unchanged drug enters the circulation from
site of administration
Distribution: Reversible transfer of drug from one location (e.g. vascular) in the
body to another (e.g., extravascular)
Metabolism: Transformation of a drug into daughter compound(s)
Excretion: Removal of drugs/metabolites from the body

Absorption

Distribution
Disposition
Metabolism
+ = Elimination
Excretion
 ADME = Pharmacokinetic processes
• As the drug moves through the body, the body acts on the drug:
absorption, distribution, metabolism and excretion (ADME)

• ADME are the processes of pharmacokinetics (i.e. the way the body
handles the drug)

• Drugs need to be absorbed unless given directly into the circulation

• Drug must get from the site of administration to the site of action in a
timely/predictable manner

Importance of ADME
• Gives us insight into the time course of the absorption, distribution,
metabolism and elimination/excretion of the drug

• Allows us to build better treatment plans- ensures that a positive

therapeutic outcome is achieved
• Minimise adverse reactions to medications- deep understanding of ADME
allows safe medication doses to be estimated
 Drug absorption
• Absorption requires drugs to cross some physiological barriers (layers of cells with
semi-permeable, lipophilic membranes)
• Most absorption occurs through cells but, some occur between cells
• For maximum therapeutic effect, it is preferable if drugs are absorbed in a timely and
predictable manner
drug drug

cells

through cells between cells

(transcellular) (paracellular)
Unionised, lipophilic Ionised; mw~20,000

Mechanisms involved in the movement of drugs from the site of administration to the site
of action by passive transcellular diffusion, facilitated-/carried-mediated diffusion through
cells and active transport through cells
 Mechanisms involved in the absorption of drugs
1. Passive transcellular diffusion: most common - uncharged and unionised;
e.g., GI absorption. Orally administered drug → stomach → small
intestine

2. Facilitated-carrier mediated diffusion: example, sodium-dependent

glucose, amino acid transport; amino acid transporter transports β-
lactam, ACE inhibitors, zidovudine

Factors affecting the rate of diffusion of a drug:

• Size of the drug molecule and its configuration
• Chemical structure (lipid solubility, ionisation) of the molecule
• Surface area of absorption site
• Cell membrane is lipid – diffusion occurs more readily if the drug is
lipid-soluble (lipophilic); propine or dipivefrin (lipophilic prodrug) →
adrenaline

Rate of diffusion = surface area x concentration difference x permeability

molecular size
Fick’s law
lipid solubility
presence of charged or ionisable groups
 Drug absorption
3. Active transport: very few medicines; example, choline uptake,
levodopa (treats Parkinson’s disease)

Choline + acetate  acetylcholine (ACh)

Uptake of choline into cholinergic nerves is essential for synthesis of ACh

– all cells have low affinity choline uptake system

– cholinergic nerves (i.e., nerves that release acetylcholine) have a
high affinity uptake system for choline

• Hemicholinium blocks the high affinity active transport system that gets
choline into nerves
– This gradually depletes ACh levels due to decreased release
– Thus, nerve function is impaired
 Drug absorption
Sodium pump (Na+/K+ ATPase)
• Important in maintaining ionic balance in excitable cells e.g. nerves,
muscle

• When action potentials pass through excitable cells, Na+ ions enter the
cell causing depolarisation and K+ ions leave the cell causing
repolarisation

• Between action potentials the “sodium pump” restores normal ionic

balance

• Digoxin inhibits Na+/K+ ATPase

– increases the force of contraction of the heart
How?
– increases [Na+]i, this increases Ca2+ influx which increases the force of
contractility of the heart
– Digoxin is used to treat “heart failure”
 Drug absorption
General factors affecting the absorption of drugs:
• Patient condition
• Gut bacteria
• Other substances
• Enterohepatic recirculation
• First pass effect by gut wall, liver or during absorption

Patient condition
• GI motility, GI pH, diseases of stomach and intestines
• Bacterial flora
• Level of perfusion of organs and tissues
• Genetics
• Kidney, cardiovascular, liver function
 Drug absorption
Gut bacteria
Drug → liver, where it reacts with conjugating agents (glucuronic acid) →
conjugate (e.g. glucuronide)
• Glucuronide in the liver enters the duodenum with bile
• Drug (glucuronide) encounters gut bacteria in the intestine
• Gut bacteria has enzymes which can act on the conjugate → drug release
 drug is reabsorbed – so, drug spends a long time in the body

Other substances/drug-drug interactions

• Oral tetracycline with milk or antacids (Ca2+, Al3+ ions) reduce the
absorption - chelation
• Food can reduce the absorption of some drugs (e.g., enteric coated
aspirin)

• Oral contraceptive steroids co-administered with some anti-microbials

agents→ contraceptive failure and pregnancy
 Drug absorption: Enterohepatic recirculation
Enterohepatic recirculation
• Occurs with small less polar drugs
• Drugs/drug conjugates entering the gut with the bile salts may be
reabsorbed and later excreted in the urine or even returned to systemic
circulation or the bile

How?
• Glucuronide conjugates may be cleaved by gut enzymes (e.g., -
glucuronidase) to release parent lipid-soluble drug, which is then
available for reabsorption
 First pass effect on drug absorption
First pass effect by gut wall, liver or during absorption
GIT
Systemic circulation

hepatic vein

Portal vein

• First pass: drug removed by metabolism the first time it encounters the
organ (e.g., GIT/liver) involved in its removal/metabolism

• For example, the liver’s cytochrome P450 enzymes are taking the drug
out completely/partially, e.g. progesterone

Importance of first pass metabolism

• Effects on regular drugs
• Effects on prodrugs
 Drug absorption: Lipinski’s rule of 5
A rule-based approach to ADME optimisation – useful in the setting of drug
discovery and development

Lipinski’s rule of 5: An orally-active drug likely has no more than one violation
of the Lipinski’s rule of 5 which is:

Some criticisms of the Lipinski’s rule of 5:

 The rule does not adequately predict pharmacological activities
 The rule of 5 probably limits creativity
 ADME optimisation might minimise desirable properties for receptor binding
Examples of drugs that did not obey the Lipinski’s rule of 5

Ledipasvir

Cyclosporine A

Venetoclax
 Drug absorption- Ion trapping
• Ion trapping refers to the phenomenon when an ionised drug becomes
concentrated in the ionising solution
• Acidic drugs are absorbed efficiently from the stomach (pH = 1-2)
• Basic drugs are absorbed less efficiently in the stomach
• Changes in pH may lead to the ionisation of a drug and consequently
make it less lipophilic

Note that the same principles apply to the renal excretion of drugs:
• Alkaline urine traps and enhances the urinary excretion of acidic drugs
• So, alkalinising the urine is used as a strategy to treat aspirin overdose
• This is because aspirin is a weak acid; when exposed to alkaline urine,
it is ionised which makes it poorly reabsorbed and thus, readily
excreted
 Drug absorption – Ionisation of drugs
• Most drugs are weak acids or bases and are, therefore, ionisable

Aqueous environment
basic
Weak acidic drug AH A- + H +
- Proton donor acidic
acidic
Weak basic drug B BH+ + OH-
- Proton acceptor basic

Extent of ionisation depends on:

. pKa of the drug in question
. pH of the aqueous environment the drug happens to be in
- Acid / base dissociation constant of the drug
 Drug absorption- Ionisation of drugs
• To diffuse across cell membranes, medicines must be uncharged (unionised)
• Unionisable and lipophilic drugs are absorbed most effectively
• Ionised (charged) drugs are absorbed least effectively

acidic
drug
A - + H+ AH AH A - + H+

basic
drug
BH+ + OH- B B BH+ + OH-
Henderson-Hasselbalch equation and drug absorption
 Henderson-Hasselbalch equation predicts the extent of ionisation for bases
and acids, which has a bearing on the absorption of drugs

 Acidic environment makes acidic drugs more unionised and easily absorbed
 Alkaline environment makes basic drugs more unionised and easily
absorbed

For acids: pH = pKa + log [ionised]/[unionised]

For bases: pH = pKb + log [ionised]/[unionised]

pKa = pH at which 50% of the drug ionised

• Henderson-Hasselbalch equation provides a relationship between the pH

of acids (in aqueous solutions) and their pKa (acid dissociation constant)

• Thus, the pH can be estimated if the concentration of the acid and its
conjugate base, or the base and the corresponding conjugate acid, are
known
 Henderson-Hasselbalch equation - Solved example
For acids: pH = pKa + log [ionised]/[unionised]

For bases: pH = pKb + log [ionised]/[unionised]

pKa = -logKa

If a buffer solution is made from 0.5M CH3COOH and 0.78M CH3COO– and the
acid dissociation constant of CH3COOH is 2.4*10-5, what is the pH of the buffer
solution?
Solution:
 Henderson-Hasselbalch equation: pH = pKa + log([CH3COO–]/[CH3COOH])
 Ka = 2.4*10-5 ⇒ pKa= -log(2.4*10-5) = 4.6
 If we substitute the values, the answer becomes:
pH = 4.6 + log(0.78M/0.5M) = 4.8
 Drug absorption - ionisation

Aspirin (acetylsalicylic acid); mw is 180.16

• Aspirin: quite well absorbed in the unionised form in the stomach, but
much better absorbed in the small intestine

• The pH is 5.5-7.5 in the small intestine; this increases the degree of

ionisation of aspirin in the small intestine

• However, the good blood supply and surface area of the small intestine
overcome the chemistry of the drug
 Absorption of aspirin at the gastric mucosa

Stomach Circulation
pH = 1 pH = 7.4

Asp- + H+ HAsp HAsp Asp- + H+

99.7% 0.1% 99.9%
0.3%
Gastric mucosa

o Aspirin is weak acid

HAsp Asp- + H+
o pKa = 3.5
o For acids: pH = pKa + log [ionised]/[unionised]
 Absorption of aspirin: gastric mucosa vs plasma
Aspirin is a weak acid, pKa of 3.5
Definition of pKa: pH at which 50% of drug is in the ionised state

The reaction: HAsp (unionised) H+ + Asp- (both ionised)

In stomach:
• Environment pH = ~1.4 (<pKa of aspirin, aspirin acts as a proton acceptor)
• Reaction is driven to the left, forming un-ionised HAsp
• Unionised HAsp is lipid-soluble, crosses gastric mucosa into plasma
• Much of the aspirin is absorbed in GI tract due to large surface area

In plasma:
• Environment pH = ~7.4 (>pKa of aspirin, aspirin acts as a proton donor)
• Reaction is driven to right, forming ionised Asp-
• Asp- cannot pass back into stomach

Asp- is ‘Ion-trapped’ in plasma

Properties of aspirin and what influences its absorption
• Aspirin: Acidic, a small molecule
To enter the bloodstream, aspirin must pass through the membrane lining the
stomach and the small intestine
Stomach: large surface area, thin, moist, and highly vascularised
• pKa of aspirin is 3.5
• Remains un-dissociated, neutral, and lipid soluble in the stomach (pH ~ 1)
• Thus, it is expected to be absorbed faster through lipid bilayer of cell
membranes lining the stomach than through cell membranes in the small
intestine (pH~7)

Intestine: large surface area

• pKa of aspirin 3.5
• COOH of aspirin is expected to dissociate into COO- and H+ at the intestinal
pH of ~7
• Becomes negatively charged
• Not easily absorbed through the lipid bilayer of the intestinal cell
membrane
 Can basic drugs be given orally?
Yes – unless they are very basic or permanently ionised
• Basic drugs (morphine, pethidine) are absorbed poorly from stomach
(pH 1-2; 500-800cm2)
• However, they are absorbed better from the intestine (pH 5.5-7.5)
• The absorptive surface area of the small intestine (200-250m2)
compensates for low absorption efficiency
• Many drugs are absorbed in the intestine