PK-7

Fattori fisiologici legati all’assorbimento dei farmaci

 Systemic Absorption of drugs
Systemic absorption of a drug depend upon
1.Physicochemical properties of the drug (drug properties)
2.Nature of “Drug Product” (drug product properties)
3.Anatomy and Physiologic functions at the site of absorption (body properties)

Absorption of drug to reach general circulation requires passage through or

around one or more layers of cells.

For absorption into the cell a drug must traverse the cell membrane.

Transcellular absorption is the process of a drug movement across a cell.

Some polar small molecules are not able to cross the cell membrane, but go
through gaps or tight junctions between cells (paracellular drug absorption)
 Systemic Absorption of drugs

Epithelial permeability
•TRANSCELLULAR
• PARACELLULAR

Limitation factors
•apical pumps (pGP, etc.)
•Intracellular methabolism
 Cell Membrane
• surrounds the entire cell (plasma membrane)
• boundary between cell and interstitial fluid
• membrane enclose most of the cell organelles
• is a selective barrier to passage of molecules (semipermeabile)
• water, very small molecules and lipid-soluble molecules pass through,
• higly charged molecules and large molecules (proteins) and protein-bound drugs
don not cross
• 7-10 nm thickness
• Fluid mosaic model (Singer & Nicolson, 1972)
 Passive diffusion (1)
Passive diffusion: a process of diffusion from a region of higher concentration to a region
of lower concentration
Passive: no external energy is expended

The rate of transfer is called FLUX.

Fick’s Law

dQ D  A  K Chigh A Clow
 Chigh  Clow 
dt h
h
Where
Q is the amount of compound,
D is the diffusion coefficient,
K is the lipid water partition coefficient of drug in the membrane
A is the membrane surface are
h is the membrane thickness
Chigh- Clow is the difference of concentration
 Weak electrolytes (1)
• The more lipid-soluble compounds tend traverse cell membranes more easily than less-
lipid soluble or more water-soluble compounds

• For drugs that act as are weak electrolytes such as weak acids or weak bases, the
extent of ionization influences the rate of permeability (P).

• The ionized species of the drug contains a charge and is more water-soluble than the
non-ionized species, which is more lipid soluble

• The extent of ionization of a weak electrolyte will depend on both the pK a of the drug and
the pH of the medium in which the drug is dissolved

• Henderson and Hasselbalch use the following expression to describe weak acids and
weak bases partitioning relationship between pK a and pH:

for weak acids for weak bases

salt A Ratio 
 base   RNH 2   10( pH  pk )
Ratio    10( pH  pk a )
 salt  RNH 3 
a

acid HA
 Weak electrolytes (2)
If we suppose that pKa is known, we can calculate the between ionized and non-ionized
species

For example at plasma pH (pH= 7.4) salycilic acid (pK a = 3.0) would exist mostly in its
ionized or water-soluble form:

salt A
Ratio    10( 7.43.0)  104.4  2.51104
acid HA

The total drug concentration at either side of a membrane should be the same at
equilibrium, assuming Fick law of diffusion is the only distribution factor involved.

For diffusible drugs, such as non-electrolyte drugs or drugs that do not ionize, the drug
concentrations at either side of the membrane are the same at equilibrium.

For electrolyte drugs or drugs that ionize, the total drug concentrations on both sides of
the membrane are not equal at equilibrium if the pH of the medium differs on respective
sides of the membrane.
 Weak electrolytes (3)
For example consider concentration of salycilic acid in the stomach (pH= 1.2) as
opposed to the concentration of salycilic acid in the plasma (pH= 7.4)

Gastric juice (pH= 1.2) Plasma (pH= 7.4)

RCOOH RCOOH

RCOO- + H3O+ RCOO- + H3O+

In the plasma at pH= 7.4 RCOO 

Ratio   10( 7.43.0 )  104.4  2.51104
RCOOH

RCOO 
In the gastric juice at pH= 1.2 Ratio   10(1.23.0)  10 1.8  1.58 10 2
RCOOH
 Weak electrolytes (4)
According to the pH-partition hypotheses, if pH in one side of a cell membrane differs
from the pH on the other side of the membrane, then:
1.The drug (weak acid or base) will ionize to different degrees on respective sides of the
membrane
2.The total drug concentration (ionized plus non-ionized drug) on either side of the
membrane will be unequal
3.The compartment in which the drug is more highly ionized will contain the greater total
drug concentration

Relative concentrations of a weak acid drug and a weak base drug as affected by pH

Salicilic acid (pKa = 3.0) Pentobarbital (pKa = 8.0)

DRUG Gastric Plasma DRUG Gastric Plasma
Juice (pH=7.4) Juice (pH=7.4)
(pH=1.2) (pH=1.2)
RCOOH 1 1 RNH2 0.00000016 0.25

RCOO- 0.0158 25100 RNH3+ 1 1

Total 1.0158 25101 Total 1.00000016 1.25

 Carrier-Mediated Transport (1)
Specialized carrier-mediated transport systems are present in the body, especially in the
intestine for the absorption of ions and nutrients required by the body.

Carrier-mediated transport can be

Drug Drug

ATP
Drug Pi Drug

ADP

Drug + Pi Drug

Drug Drug

active transport or facilitated diffusion

 Epithelial Models (1)
Epithelial models are used to estimate trans-epithelial permeability,

Caco-2 cells
 Epithelial Models (2)
Caco-2 cells

dQ
 PA -B  A  C A
dt

dQ Q
PA -B  dt  t
A  CA A  CA

P
dQ Q (cm/sec)

PB-A  dt  t
A  CB A  CB

 mg
 P  2  sec

 mg   mL

 cm3 

 cm
cm    mg / mL  sec  cm    mg  sec cm   sec
2 2
 Epithelial Models (3)
Caco-2 cells (oral absorption vs. Papp)
 Oral Drug Absorption
Anatomic and Physiologic Considerations (1)

Enteral System: from mouth to the

anus.
Physiological processes:
1.Secretion includes the transport of
fluid, electrolytes, peptides and
proteins into the lumen;
2.Digestion is the breackdown of food
components into smaller structures in
preparation of absorption
3.Absorption is the entry of
constituents from the lumen of the gut
into the body. Absorption may be
considered the net resul of both the
lumen-to blood and the blood-to-lumen
transport movements.
Drugs administered orally pass
thorough various parts of the entral
canal
 Oral Drug Absorption
Anatomic and Physiologic Considerations (2)

Oral Cavity:
•Saliva has pH = 7.0 and contains salivary amylase whigh digests starches .
•About 1500 ml/day secreted.
Esophagus:
•pH is between 5 and 6, lower part ends with esophageal spincter which
prevents acid reflux from the stomach
Stomach:
•innervated by vagus nerve.
•Local nerve plexus, hormones, mechanoreceptors sensitive to the starch
of the GI wall and chemoreceptors control the regulation of gastric
secretions, including acid and stomach empting.
• Fasting pH= 1.5-2.0. Secreted pepsin initiates protein digestion.
•Basic drugs are rapidly solubilised in presence of acid.
•Stomach empting is influenced by the food content and osmolarity (fatty
and mono- di- glycerides dilay gastric empting, etc.)
 Oral Drug Absorption
Anatomic and Physiologic Considerations (3)

Duodenum:
•Duodenal pH between 6.0 and 6.5 due to the presence of bicarbonate
that neutralizes the acidic chime emptied from the stomach.
•pH is optimum for enzymatic digestion of protein and peptide food.
•A common duct from the pancreas and the gallbladder enters into the
duodenum. Pancratic fluid is rich of digestive enzymes and bile is rich of
biliary acids
• The complex fluid medium in duodenum helps to dissolve many drugs
with limited aqueous solubility
•The diuodenum is the site where many ester prodrugs are hydrolyzed
during absorption and where presence proteolitic enzymes makes protein
drugs unstable.
•Duodenum offers a high surface are for absorption.
 Oral Drug Absorption
Anatomic and Physiologic Considerations (4)

Surface area in Duodenum

 Oral Drug Absorption
Anatomic and Physiologic Considerations (5)

Jejunum
•Is the middle portion of the small intestine
•pH is between 6.5 and 7.0
•Digestion of proteins and carbohydrates continues after receiving
pancreatic juice and bile in duodenum
•Jejunum has fewer contraction than Duodenum and is the preferred
portion of small intestine for in vivo drug-absorption studies

Ileum
•Is the terminal part of small intestine.
•Ileum has fewer contractions than duodenum (similar to ileum)
•The pH is about 7.0 with the distal part as high as 8.0
•Due to the presence of bicarbonate secretion acid drugs will dissolve in a
medium rich of bile acids. This medium help dissolution of fats and
hydrophobic drugs
 Oral Drug Absorption
Anatomic and Physiologic Considerations (6)
Colon
•Colon lacks villi and has limited drug absorption due to the more viscous
and semisolid nature of lumen content
•Lined with mucin acting functioning as lubricant and protectant
•pH in these region is between 5.0 and 7.0
•Few drugs are absorbed in these region (metoprolol and theofilline)
•Drugs that are absorbed well in this region are good candidated for an
oral sustained-release dosage form
•Anaerobic and aerobic microorganisms contained in colon may
metabolize drugs (L-dopa and Lactulose)
Rectum
•About 15 cm long
•In absence of faecal material has small amount of fluid (2 mL) with pH
about 7.0
• Perfused by superior, middle and inferior hemorroidal veins
•The inferior haemorrhoidal vein (closest to the anal shincter) and the
middle haemorrhoidal vein feed in the vena cava and back to the hearth
(no first pass in the liver). Superior haemorrhoidal vein feeds into the
mesenteric vein to the hepatic portal vein (first pass in the livers)
 Oral Drug Absorption
Anatomic and Physiologic Considerations (7)
 Routes of Drug Administration: Parenteral (1)

Route Bioavailability Advantages Disadvantages

Intavenous Bolus (IV) Complete (100%) Drug is given for Increased chance for
systemic drug immediate effect advese reaction.
absorption. Rate of Possible anaphylais
Bioavailability
considered
instantaneous
Intravenous Infusion Complete (100%) Plasma drug levels Requires skills in
(IV inf) systemic drug more precisely insertion of infusion
absorption. Rate of controlled. set
Bioavailability May inject large fluid Tissue damage at site
controlled by infusion volumes. of injection
pump May use drugs with (infiltration, necrosis
poor lipid solubility or sterile abscess)
and/or irritatinng
drugs
 Routes of Drug Administration: Parenteral (2)

Route Bioavailability Advantages Disadvantages

Intramuscular Rapid from aqueous Easier to inject than Irritating drugs may
injection (IM) solution intravenous injection be very painful
Slow absorption from Larger volumes may Different rates of
non-aqueous be used when absorption
solutions. compared to depending on muscle
subcutaneous group injected and
injection blood flow

Subcutaneous Prompt from Generally used for Rate of drug

injection (SC) aqueous solution insulin injection absorption depends
Slow absorption from upon blood flow and
repository injection volume
 Routes of Drug Administration: Enteral

Route Bioavailability Advantages Disadvantages

Buccal or sublingual Rapid absorption from No first-pass effect Some drugs may be
(SL) lipid-soluble drugs swallowed
Not for most drugs or
drugs with high doses
Oral (PO) Absorption may vary Safest and easiest Some drugs may have
Generally slower route of drug erratic absorption, be
absorption rate administration instable in the
compared to IV bolus May use immediate- gastrointestinal tract,
or IM injection release and or be metabolized by
modificate- elelase liver prior to systemic
drug products absorption
Rectal (PR) Absorption may vary Useful when patient Absorption may be
from suppository cannot swallow erratic.
More reliable medication Suppository may
absorption from Used for local and migrate to different
enema (solution) systemic effects position
Some patients
discomfort
 Other Routes of Drug Administration

Route Bioavailability Advantages Disadvantages

Transdermal Slow absorption, rate Transdermal delivery Some irritation by
may vary system (patch) is easy patch or drug
to use Permeability of skin
Used for lipid-soluble variable with
drugs with low dose condition, anatomic
and low MW site, age and gender
Inhalation Rapid absorption May be used for local Particle size of drug
Total dose absorbed is or systemic effects determines anatomic
variable placement in
respiratory tract
May stimulate cough
reflex.
Some drugs may be
swallowed