ABSORPSI OBAT

In this chapter we will:

• review the structure and function of biological

membranes

• discuss the factors influencing the transport of drugs

through them
 Biological membranes and drug transport

Biological membranes

Membrane structure

• Figure 1 shows a diagram of the fluid mosaic model of a

biological membrane.
• The fluid mosaic model, in particular, allows the
protein–lipid complexes to form either hydrophilic or
hydrophobic ‘gates’ to allow transport of materials of
different characteristics.
Figure 1 Diagrammatic representation of
the fluid mosaic model of a biological membrane.
 Biological membranes and drug transport

Biological membranes
Cholesterol

• Cholesterol is a major component of most mammalian biological

membranes.
• Its shape allows it to fi t closely in bilayers with the hydrocarbon
chains of unsaturated fatty acids.

• Its removal causes the membrane to lose its structural integrity

and to become highly permeable.
• It complexes with phospholipids and reduces the permeability of
phospholipid membranes to water, cations, glycerol and glucose.
 KEY POINTS
• The main function of biological membranes is to contain the
aqueous contents of cells and separate them from an aqueous
exterior phase.
• Membranes are lipoidal in nature.
• To allow nutrients to pass into the cell and waste products to
move out, biological membranes are selectively permeable.
• There are specialised transport systems to assist the passage
of water-soluble materials and ions through their lipid interior.
• Some drugs are absorbed by transport systems and do not
necessarily obey the pH partition hypothesis.
 KEY POINTS
• Lipid-soluble agents can pass by passive diffusion through the
membrane.
• Biological membranes are composed of bilayers of
phospholipids and cholesterol or related structures.

• Embodied in the matrix of lipid molecules are proteins,

generally hydrophobic in nature.
• Membranes have a hydrophilic, negatively charged exterior
and a hydrophobic interior.
 KEY POINTS
• Absorption generally requires the passage of the drug in a
molecular form across one or more barrier membranes and
tissues.
• Most drugs are administered as solid or semisolid dosage forms.
• Tablets or capsules will disintegrate, and the drug will then be
released for subsequent absorption.
• Many tablets contain granules or drug particles which should
deaggregate to facilitate the solution process.
• If the drug has the appropriate physicochemical properties, it
will pass by passive diffusion from a region of high concentration
to a region of low concentration across the membrane.
• Soluble drugs can, of course, also be administered as solutions.
• Drug absorption is controlled by the nature of the
membrane, its degree of internal bonding and rigidity, its
surface charge and by physicochemical properties of the
drug.

• Note that cellular efflux mechanisms centred on P-

glycoproteins exist.

• Some drugs are ejected from cells by these ‘pumps’ so that

these drugs have a lower apparent absorption than
predicted on physicochemical grounds.
 Lipophilicity and absorption
• If the percentage absorption
versus log P is plotted a parabolic
relationship is obtained, with the
optimum value designated as log
Po (Figure 2).
• The optimal partition coefficient
differs for different absorbing
membranes.
Drugs with high log P values
• Drugs with high log P values are
proteinbound, have low aqueous
solubility and bind to extraneous
sites.
• They have a lower bioavailability
than anticipated from their log P,
giving rise to the parabolic curve
shown in Figure 2.
Drugs with low log P values
• May be too hydrophilic to have
any affinity for the membranes
and hence may be poorly
absorbed.
Figure 2 Typical activity–log P plot.
 Molecular weight and drug absorption

• The larger drug molecules are, the poorer will be their absorption.
• Lipinski devised a rule of five defining drug-like properties.

• Good oral absorption is more likely when:

o the drug molecule has fewer than 5 hydrogen bond donors (–OH
groups or –NH groups)
o the molecular weight of the drug is less than 500
o log P of the drug is less than 5
o there are fewer than 10 H-bond acceptors.

but note:
o Compounds that are substrates for transporters are exceptions to the rule.
 Permeability and
the pH-partition hypothesis
Assumption
• Only drugs in their unionised form (more lipid-soluble) pass
through membranes.
• As most drugs are weak electrolytes it is to be expected that
the unionised form (U) of either acids or bases, the lipid-
soluble species, will diffuse across the membrane, while the
ionised forms (I) will be rejected.

Calculation of percentage ionisation

• For weakly acidic drugs (such as aspirin and indometacin) the
ratio of ionised to unionised species is given by the equations:
• For weakly basic drugs the equation takes the form:
 Discrepancies between
expected and observed absorption

• Absorption is often much greater than one would expect, although the
trend is as predicted.
• For example, absorption of acetylsalicylic acid is 41% at pH 4 (although only
24% is in unionised form) and 27% at pH 5 (only 3.1% is in unionised form).

• Two possible explanations:

1. Absorption and ionisation are both dynamic processes so that even small
amounts of unionised drug can be absorbed and are replenished.
2. The bulk pH is not the actual Ph at the membrane. A local pH exists at
the membrane surface which differs from the bulk pH. This local pH is
lower than the bulk because of the attraction of hydrogen ions by the
negative groups of the membrane components (see below).
 Problems in the quantitative application of
the pH-partition hypothesis
• There are several reasons why the pH-partition hypothesis
cannot be applied quantitatively in practical situations:

• Variability in pH conditions

o Although the normally quoted range of stomach pH is 1–3,

studies using pH-sensitive radiotelemetric capsules have
shown a greater spread of values, ranging up to pH 7.
o The scope for variation in the small intestine is less, although
in some pathological states the pH of the duodenum may be
quite low due to hypersecretion of acid in the stomach.
 Problems in the quantitative application of
the pH-partition hypothesis
• pH at membrane surfaces

1. pH at the membrane surface is lower than that of the bulk

pH, hence the appropriate pH has to be inserted into
equations, and the solubility of drug will change in the
vicinity of the membrane.

2. The secretion of acidic and basic substances in many parts

of the gut wall is also a complicating factor.
 Problems in the quantitative application of
the pH-partition hypothesis

• Convective water flow

1. The movement of water molecules, due to differences in

osmotic pressure between blood and the contents of the
lumen and differences in hydrostatic pressure between
lumen and perivascular tissue, affects the rate of
absorption of small molecules.
2. Absorption of water-soluble drugs will be increased if
water flows from the lumen to the serosal blood side
across the mucosa, provided that drug and water are using
the same route.
3. Water movement is greatest within the jejunum.
 Problems in the quantitative application of
the pH-partition hypothesis

• Unstirred water layers

1. A layer of relatively unstirred water lies adjacent to all

biological membranes.

2. During absorption drug molecules must diffuse across this

layer, which is an additional barrier.
 Problems in the quantitative application of
the pH-partition hypothesis
• Effect of the drug

1. The drug must be in its molecular form before diffusional

absorption processes take place.
2. Basic drugs are therefore expected to be more soluble than
acidic drugs in the stomach.

3. Although the basic form of a drug as its hydrochloride salt

should be soluble to some extent in this medium, this is
not always so.
4. The free bases of chlortetracycline and methacycline are
more soluble than their hydrochloride salts in the stomach.
 Problems in the quantitative application of
the pH-partition hypothesis
• Other complicating factors

1. The very high area of the surface of the small intestine also
upsets the calculation of absorption based on
considerations of theoretical absorption across identical
areas of absorbing surface.
2. Co-administration of drugs such as cimetidine can raise
stomach pH from below 2 to near neutrality.
3. The following may not be absorbed as expected:
drugs which are:
• unstable in the gastrointestinal tract (for example,
erythromycin)
 Problems in the quantitative application of
the pH-partition hypothesis
• Other complicating factors
3. The following may not be absorbed as expected:
drugs which are:
• unstable in the gastrointestinal tract (for example,
erythromycin)
• metabolised on their passage through the gut wall
• hydrolysed in the stomach to active forms (prodrugs)
• bound to mucin to form complexes with bile salts
• in the charged form, which interacts with other ions to
form absorbable species with a high lipid solubility
• ion pair formation.
 KEY POINTS
• The nature of the formulation often has a large effect on drug
absorption from some sites.
• The important features are always the interplay between:
1. drug
2. vehicle (formulation)
3. the route of administration.
• The same drug may be absorbed from different sites, often in quite
different amounts.
For example:
cocaine with a P of 28 requires a sublingual/s.c. dosage ratio of 2 to
obtain equal effects;
atropine with a P of 7 requires eight times the s.c. dose;
codeine (P ∼2) over 15 times the s.c. dose must be given
sublingually.
 Penembusan barier fisiologis
• Dalam perjalanannya di tubuh obat harus menembus beberapa
jenis barier.
• Barier ini dapat berupa lapisan tunggal sel (ex:epitel intestinal)
atau beberapa lapis sel (ex: kulit), atau membran sel itu sendiri
(untuk mencapai reseptor intraseluler).
• Obat dapat melintasi barier dgn menembus sel (transeluler) atau
melewati celah di antara sel (paraseluler)
 Transport obat transeluler
• Untuk menembus sel atau mencapai bagian dalam sel, obat
harus melewati membran sel.

• Membran sel (membran plasma) merupakan lipid bilayer yg

mengandung juga karbohidrat dan protein.

• Mekanisme utama penembusan membran sel adalah difusi pasif,

transport termediasi (difusi terfasilitasi & transport aktif) dan
transport vesicular.
Transport Transeluler
Transport Para & Transeluler
The relation between drug absorption, distribution,
metabolism and excretion, and
the concentration of drugs at their site of action.
 The enterohepatic circulation of drugs.
Only small amounts of the absorbed drug and its conjugates
escape recirculation and enter the systemic circulation.
• Calvey. 2007. Drug Absorption, Distribution and Elimination:
Chapter 1.
• Wang; Siahaan; Soltero. 2005. Drug Delivery - Principles and
Applications.
• Attwood; Florence. 2008. Physical Pharmacy.