Absorption of Drugs, Oral Bioavailability and Presystemic Elimination

Question 1

Absorption from GIT

Mechanisms

Answer 1

Diffusion
Carrier Mediated: 2ary and 3ary active
Example: DMT, peptide, H+ dep folate
R Mediated Endocytosis

Question 2

Absorption from GIT

Influencing Factors

Answer 2

Motility of GIT
Gastric emptying: how soon drug reaches prox small
intestine (large absorptive surface)
Intestinal peristaltic movements; diarrhoea, constipation

Luminal pH
Ionised-> lipid soluble, can diffuse
pH Entrapment: Amphetamine: protonated in stomach
-> can’t diffuse back-> can aspirate in intoxication

Absorption of weak acids (ex aspirin) can start in
stomach (favourable ionised/non ionised ratio)

Luminal Content: Quantity
Typically better absorption of drugs if stomach empty

Luminal Content: Quality
Low acidity of stomach: antifungals: no dissolution
-> no absorption
High fat meals promote dissolution of hydrophobic lipid
drugs

High protein meal-> competitive inhibition of absoprtion
Example: L-DOPA via L Type AA Transporter

High intake fruit juices: decreased fexofenadine
absorption via OATP due to inhibition thereof

High Ca intake: decrease absorption of tetracyclines as
they form nonabsorbably chelates

Adsorbents (ex charcoals) used to decrease absorption of drugs after oral overdose

Question 3

Oral Bioavailability

Answer 3

Fraction of orally admin. dose that reaches systemic circulation in unchanged form

F= (AVC: P.O.)/(AVC: IV)

F= 0: no molecules reach systemic circulation

Question 4

Potential Causes of Incomplete Bioavailability

Answer 4

Incomplete release of drug from tablet/capsule..
Degradation of drug in lumen
Ex by hydrolysis, oxidation

Poor solubility of drug in intestinal fluids
Poor diffusibility (highly ionised)

Presystemic elimination (1st pass metabolism)
Intestinal Mucosa: via biotransformation
Catalysed by: CYP, MAO A, SULT, UGT

Intestinal Mucosa: via export
Pgp/ MDR1

Liver: Biotransformation
CYP

Consequences of low oral bioavailability
Low F unfavourable for drugs that reach site of action
via systemic circulation
Low F favorable for drugs whose target is presystemic
ex: Statins: HMG CoA Reductase Inhibitors

Inhibition of presystemic elimination-> increased oral bioavailability
Example: Verapamil competitively inhibits Pgp

Question 5

Absorption from Oral, Nasal, Rectal Mucosa

Answer 5

Mechanism: Diffusion
Small absorptive surfaces
Drugs aren’t exposed to HCl and high conc of digestive
enzymes

Drugs aren’t subjected to presystemic elimination

Oral: Ex: Nitroglycerine

Nasal: Oligo and Nonpeptides
Ex: Oxytocin, Estradiol

Rectal: given when oral admin is suboptimal
exposure of gastric mucosa or liver undoes
oral dosing-> high 1st pass
Ex: ergotamine: reaches high blood level rectally

Question 6

Absorption from Skin

Answer 6

Mechanism: Diffusion

Influencing Factors
Lipid solubility and concentration-> chemical
Site of exposed area
infants lack st corneum and have rel large body
surface area

Thickness of St Corneum: main diffusion barrier
Dermal circulation: increased by
sauna, hot weather, rubbing, inflammation

Question 7

Absorption from Lungs

Answer 7

Mechanism: Diffusion

Chemical Factors
Inhaled Conc
Lipid Solubility

Biological Factors
Absorptive surface area
Small diffusion distance
Large pulmonary flow

Application of: gases, vapour, small particle size powder

Particle size determines site of deposition
>10microm: upper airways
1-5 microm: Bronchioles-> asthmatics
<1 microm: Alveolar space-> readily absorbed and
causes systemic effect

Systemic effect can be desirable in cases of ex inhalation anaesthetics