SISTEM PENGHANTARAN OBAT

How do we measure a drug’s lipophilicity?

We can simulate the biological membrane by shaking the drug with
an immiscible mixture of a lipophilic oily solvent (octanol, the lipid
bilayer) and a hydrophilic solvent (water, the extra/intra-cellular fluid).

The partitioning between the two layers can then be calculated.

Partition Coefficient, P = [Oil] / [Aqueous], where [ ] = concentration

And it is normally expressed as a log:

Log P= log10 (Partition Coefficient)

The higher the Log P value the more lipophilic the drug
i.e. more of the drug dissolves in the oil.

Most drugs ionise and, in these cases, the pH of the

medium that the drug is in will have a profound effect on
the partition coefficient.
Log P values

Nifedidine, Log P = 3.57

[oil]/[water] = 3715

Sulfisoxazole, Log P = -1.46

[oil]/[water] = 0.035
 Log P
Values of Log P that which are too high (> 6) or too low (<-2) are associated
with poor transport characteristics

 Very high Log P – poor aqueous solubility – remain in lipidic membrane

 Very low Lop P – not sufficiently lipiphilic to pass through lipid membrane

From rat colon

Log P
-0.15

0.68

1.14

1.44

1.71
Most drugs are acids or bases -
pH has a profound effect on Log P (Log D)

Ionization = decrease in lipophilicity

= decrease in absorption

Drugs encounter a range

of pH’s in the body.
 Drug absorption:
effect of inhibition of P-gp

P-gp action: reduced

absorption of substrate

Inhibition of p-gp
 More drug enters =
↑ absorption
 P-gp inhibitors
• Valspodar • Amiodarone
• Quinidine • Diltiazem
• Verapamil • Itraconazole
• Cyclosporin
• Spironolactone
• Ketoconazole
• Erythromycin
Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distribution: Focus on H1-Receptor Antagonists. Clin
Drug Invest 21 (8):587-596, 2001. Posted to Medscape 8/1/01
 P-gp Inducers
• Rifampin • Nifedipine
• Phenobarbital • Quercetin
• Clotrimazole
• Kaempferol
• Reserpine
• Galanin
• Isosafrole
• Midazolam • St. John’s Wort
• Glucocorticoids

Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distributioin: Focus on H1-Receptor Antagonists. Clin
Drug Invest 21 (8):587-596, 2001. Posted to Medscape 8/1/01
Havizur Rahman, M.Farm, Apt
Enhanced brain drug delivery
 What is Blood Brain Barrier?
• The BBB is formed by the single layer
of endothelial cells that line the inner
surfaces of capillaries in the brain.
• It is a semi-permeable capillary
membrane; that is, it allows some
materials to cross, but prevents others
from crossing.
• In the brain, the endothelial cells fit
tightly together and substances cannot
pass out of the bloodstream.
• The BBB has several important functions:
1. Protects the brain from "foreign substances" in the blood
that may injure the brain.
2. Protects the brain from hormones and neurotransmitters
3. Maintains a constant environment for the brain.
• General Properties of the BBB
1. Large molecules do not pass through the BBB easily.
2. Low lipid (fat) soluble molecules do not penetrate into the
brain.
3. Lipid soluble molecules rapidly cross the BBB into the
brain.
4. Molecules that have a high electrical charge to them are
slowed.
• Therefore:
• The BBB is selectively permeable to : Oxygen, Carbon
dioxide and glucose
• The BBB is not permeable to hydrogen ions
Strategies for drug delivery to the brain:
• Several drugs do not have adequate physiochemical
characteristics such as high lipid solubility, low molecular size and
positive charge which are essential to succeed in traversing BBB.
Carrier-mediated drug delivery

The drug or prodrug is designed to structurally resemble

the endogenous ligands of a specific transport system,

which recognizes the compound as its own substrate and

transports it across the BBB.

More than 20 carrier-mediated transporter proteins have been identified in

cerebral capillaries of the BBB
 including transporters for glucose, amino acids, choline, vitamins, low-
density lipoproteins and nucleosides
Advanced Drug Delivery and
Targeting: An Introduction
Drug Targeting Systems

Targeted-drug delivery: the delivery system

achieves site-specific drug delivery.

While the rate-controlled systems can deliver the drug

at the predetermined rate, they are generally unable to
control the fate of the drug, once it enters the body.

Site-specific drug delivery is desirable in therapeutics,

in order to improve:
drug safety
drug efficacy
patient compliance
Strategies to Increase Drug Absorption

A. Manipulation of The Drug

Physicochemical properties of a drug

which influence dug absorption include
such properties as:
lipid solubility and partition coefficient
pKa
molecular weight and volume
aqueous solubility
chemical stability
These properties can be manipulated to achieve
more favorable absorption characteristics.
Strategies to Increase Drug Absorption
B. Manipulation of The Formulation
Penetration enhancers
Types of penetration enhancer:
• chelators
• synthetic surfactants
• naturally occuring surfactants
• fatty acids
• nonsufactants
Mucoadhesives
increasing the contact time of the drug at the absorbing surface
increasing the local drug concentration at the site of
adhesion/absorption
protecting the drug from dilution and possible degradation
Strategies to Increase Drug Absorption
B. Manipulation of The Formulation
Enzymes inhibitors
The use of protease inhibitors to facilitate the
absorption of therapeutic peptides and proteins.
Ex: phosphoamidon, soyabean trypsin inhibitors,
aprotinin and the chymotrypsin inhibitor FK-448.

Other formulation strategies

The type of dosage form also profoundly
influences the bioavailability of a drug.
 TUGAS
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