biopharmaceutics

Question 1

what is biopharmaceutics?

Answer 1

the interaction of the biological system (bio) with the drug and the drug delivery system (pharmaceutics) [how to get drug from the route of administration into the blood]

Question 2

Rate-limiting steps in drug action after oral
administration

Answer 2

• Poorly water-soluble drug → Dissolutionrate-limited
• Highly water-soluble drug → Absorptionrate-limited

Question 3

Mucosal barriers separate the external environment from

Answer 3

the body’s internal milieu.

Question 4

mucosal barriers characteristics

Answer 4

These barriers are selectively
permeable : impermeable to bacteria and toxins but
permeable to water, ions and solutes, including nutrients.

Question 5

Absorption across the mucosal: 5 ways

Answer 5

A. Transcellular route: passive diffusion
B. Transcellular route: active transporter utilization
C. Paracellular route (tight junctions): passive diffusion
D. Lipid absorption via micelles / bile salts
E. Particulate absorption via GALT: Gut-Associated Lymphatic Tissue

Question 6

Larger log P = less/more lipophillic

Answer 6

more lipophillic

Question 7

Adherens junctions are what

Answer 7

junctions found beneath the tight junction which hold it loosely

both junctions are affected by Calcium ions

Question 8

Adding EDTA increases drug barriers

Answer 8

permeability

Question 9

Higher log P = more or less bioavailability usually, so more variability

Answer 9

more

Question 10

In the equation for ficks law: D is always negative as …

Answer 10

we are moving down the concentration gradient (as the drug is absorbed, this conc grad decreases, so so will the rate of diffusion)

Question 11

passive transcellular route mechanism

Answer 11

• passive diffusion (fick’s law)
  high conc on apical side of cell
  low conc inside the cell
  molecule diffuses into the cell and out the other side into the blood

Question 12

passive transcellular route drugs

Answer 12

• most drug molecules
• neutral molecules ie un-ionised
• logP important - drug must partition into membrane

Question 13

ficks law

Answer 13

J = -D (dC/dx)

Question 14

so for log p, positive numbers in the calculation =

Answer 14

hydrophobic

Question 15

what log P

Answer 15

the distribution of the drug at equilibrium
- where P is partition coefficient (often called partition ratio)
- log bc numbers are easier to handle

Question 16

drug size relationship to absorption

Answer 16

• larger molecules cross cell membranes more slowly than smaller
• tight junctions restrict the diffusion of polar molecules
• diffusion coefficient is reduced (stokes Einstein)
• active transporters responsible for fast transport of some polar molecules

Question 17

what ion has a critical role in the formation and maintenance of TJs

Answer 17

Ca2+

Question 18

tight junctions are essential for the structural integrity of what structure

Answer 18

GIT epithelium

Question 19

passive paracellular route (tight junctions)

Answer 19

Mechanism: absorption through the tight junctions

Pore size: calculated as 0.8 nm in the jejunum and 0.3 nm in the ileum and colon

Drugs: small hydrophilic molecules of molecular
diameter < 1.15 nm
* eg mannitol (0.67 nm), PEG 400 (0.53
nm), lactulose (0.95 nm)

Question 20

Transcellular route: Active transporters

Answer 20

mechanism: molecule “piggybacks” into the cell using a system designed for natural substrates such as amino acids and vitamins
N.B. often against a concentration gradient

substrates:
- L-dopa and D-cycloserine utilise the
amino acid transporter
* Angiotensin Converting Enzyme (ACE)
inhibitors utilise the oligo (2 to 3) peptide transporter (PEPT transporters)

Question 21

Transcellular route: Active transporters

Answer 21

• Transporters present on apical brush border membrane of intestinal epithelium
• Generally restricted to specific segments of intestinal mucosae * e.g.
• facilitative folic acid (folate) transporter; thiamine (vitamin B1), pyridoxine (vitamin B6), PEPT (peptide transporter), bile salt transporters

Question 22

Active versus passive transport on a graph

Answer 22

passive goes up at a similar amount, active levels off

Question 23

Lipid absorption via micelles / bile salts
Mechanism:

Answer 23

• bile salts secreted into small intestine to emulsify lipid molecules
• lipids then hydrolysed by lipases to give monoglycerides and fatty
  acids
• formation of mixed micelles of mono-glycerides, fatty acids and bile salts
• lipidic molecules absorbed by partition from micelle into the cell
• Substrates:
• poorly water-soluble drugs (ie fat-soluble)

Question 24

Lipid absorption in the intestines

Answer 24

fat droplet + bile salts -> emulsion droplets -> free fatty acids + bile salts -> micelles + bile salts

Question 25

Particulate absorption via Gut- Associated Lymphatic Tissue Mechanism

Answer 25

endocytosis via M (membranous) cells in the Peyer's patches of GALT in the small intestine * subsequent absorption into the lymphatic system * eventual distribution to liver and spleen

Question 26

Particulate absorption via Gut- Associated Lymphatic Tissue substrates

Answer 26

Macromolecules * microparticulates (< 10 μm)

Question 27

Biopharmaceutics Classification System (BCS) how many classes

Answer 27

4

Question 28

Biopharmaceutics Classification System (BCS) class 1

Answer 28

high solubility high permeability

Question 29

Biopharmaceutics Classification System (BCS) class 2

Answer 29

low solubility high permeability

Question 30

Biopharmaceutics Classification System (BCS) class 3

Answer 30

high solubility low permeability

Question 31

Biopharmaceutics Classification System (BCS) class 4

Answer 31

low solubility low permeability

Question 32

Applications of BCS (1)

Answer 32

* Formulation Development * Class I: dissolve rapidly and rapidly absorbed across gut * rapid and full absorption (good bioavailability)  formulation straightforward * Class II: dissolution rate is likely to limit absorption * Explore formulation approaches to enhance dissolution rate * Class III: dissolve rapidly, but poorly permeable * Dosage forms need to release drug rapidly to maximize the time these drugs have to permeate the GI tract * Class IV: probable very poor bioavailability * oral route might be impossible. Consider a prodrug format

Question 33

Applications of BCS (2)

Answer 33

Generic products of BCS Class I and III drugs may under certain circumstances be licensed without the need to conduct human studies on bioequivalence (BCS-based biowaiver) * Concept of bioequivalence – rate and extent of absorption is the same (within defined limits) after administration of the same molar dose * Biowaiver not applicable for different test product e.g. ester, ether, isomer, mixture of isomers. But different salt forms may be permitted.