Pharmaceutics 9 Lecture

Front 1

drug flux in different gut regions

Back 1

Unidirectional flux J is mass/time * area, so the surface area of each region is incorporated here

Front 2

Flux equation

Back 2

J- Dm*Pm*Cd/ h

Front 3

Dm

Back 3

diffusion coefficient in the barrier

Front 4

Pm

Back 4

the apparent partition coefficient between the membranes and the gut content (pH differences in individual regions are accounted for here)

Front 5

Cd

Back 5

drug concentration in the donor compartment (intestinal content)

Front 6

h

Back 6

the thickness of the barrier between the gut content and the blood in the capillaries inside the villi

Front 7

Permeabilty Coefficient I

Back 7

Characters of transport- frequently used albeit not exhaustively complete.

Front 8

Permeability Coefficient I does not account for:

Back 8

1. the delay in the start of the transport

2. accumulation in the barrier

Front 9

The permeability Coefficient can be used if sink conditions do not apply. What is an example of this?

Back 9

for slowly distributed drugs that circulate in the bloodstream

Front 10

The permeability coefficient PC describes the flux J as:

Back 10

J= PC x (Cd - Ca)

Front 11

Cd

Back 11

the drug concentration in the donor compartment( intestinal content)

Front 12

Ca

Back 12

the drug concentration in the acceptor compartment ( the blood)

Front 13

Permeability Coefficient II
(def and equ)

Back 13

by comparison with the expression for the unidirectional flux, the permeability coefficient can be as:
PC= Pm * Dm/h

Front 14

Dm (perm coef II)

Back 14

is the diffusion coefficient in the barrier (several cell layers between the gut content and the bloodstream)

Front 15

Pm (perm coef II)

Back 15

the apparent partition coefficient between the membranes and the gut content (pH differences in individual regions are accounted for here, pH partition hypothesis applies)

Front 16

h (perm coef II)

Back 16

the thickness of the barrier between the gut content and the blood in the capillaries inside the villi

Front 17

What are the units of PC?

Back 17

unit of time/distance

Front 18

Stomach pH

Back 18

1-3

Front 19

Stomach surface area

Back 19

0.1

Front 20

Stomach permeability

Back 20

+/-

Front 21

Duodenum pH

Back 21

5-6

Front 22

Duodenum surface area (m^2)

Back 22

0.1

Front 23

Duodenum permeability

Back 23

++

Front 24

Jejunum pH

Back 24

6-7

Front 25

Jejunum surface area (m^2)

Back 25

60

Front 26

Jejunum permeability

Back 26

++

Front 27

Ileum pH

Back 27

7-8

Front 28

Ileum surface area (m^2)

Back 28

60

Front 29

Ileum permeability

Back 29

+

Front 30

colon pH

Back 30

5-8

Front 31

Colon surface area (m^2)

Back 31

0.2

Front 32

Colon permeabilty

Back 32

+/-

Front 33

pH- partition hypothesis

Back 33

for ionizable drugs, non-ionized species are transported much faster than ionized species
(but ionized species are transported too)

Front 34

Cause of pH- partition hypothesis

Back 34

difference in the solvation of charged molecules in water and in the nonpolar environment

Front 35

Is the pH- partition hypothesis manifested already at the level of the two-phase systems?

Back 35

yes. ie. 1-octanol/water

Front 36

Partitioning of acids
Ions partition to lesser extent than:

Back 36

non-ionized molecules and ion pairs

Front 37

Partitioning of acids
Influence of counterions is:

Back 37

significant

Front 38

Partitioning of bases
non-ionized and ion-pairs:

Back 38

partition well

Front 39

Partitioning of bases
protonated molecules partition:

Back 39

to a lesser extent

Front 40

The apparent partition coefficient
(definition)

Back 40

each form of the drug molecule (ionized, ion-pair, nonionized) has its own partition coefficient P

Front 41

Various forms of drug molecules in the aqueous phase
We need all concentrations expressed via:

Back 41

[DH]w

Front 42

equation (5) aqueous

Back 42

qh
[DC]w= ------- * [DH]w
qc

Front 43

equation (6) aqueous

Back 43

[D-]w = qh * [DH]w

Front 44

the partition coefficient of individual drug forms
for nonionized molecules:
(7)

Back 44

[DH]o
Pdh= ----------
[DH]w

Front 45

the partition coefficient of individual drug forms
for ion pairs:
(8)

Back 45

[DC]o
Pdc= -----------
[DC]w

Front 46

Papp: Dependence on [H+] and [C+] I
-- definition (9)

Back 46

[DH]o + [DC]o
Papp=--------------------------------
[DH]w + [DC]w + [D-]w

Front 47

substituting from (5) and (6)

gets equ (10)

Back 47

Pdh * [DH]w + Pdc * [DC}o
Papp= ------------------------------------------
[DH]w + [DC]w + [D-]

Front 48

Papp: dependence on [H+] and [C+] II
changing all drug forms to [DH]w using equations (3) and (4)

equ (11)

Back 48

qh
Pdh*[DH]w+Pdc*------- * [DH] w
Papp qc
---------------------------------------------
[DH]w+qh/qc * [DH]w+qh * [DH]w

Front 49

Papp: dependence on [H+] and [C+] III
eliminating [DH]w
(12)

Back 49

Pdh + Pdc * qh/qc
Papp=----------------------------------
1 + qh/qc + qh

Front 50

the treatment (equ 3-12) is valid for acidic drugs. the dependence of Papp for basic drugs can be derived the same way

Back 50

true

Front 51

Papp: influence of counterions

Back 51

counterions can, in principle, reverse the pH profile of the apparent partition coefficient, depending on the
1. concentration
2. ion-pairing ability
3. lipophilicity

Front 52

the absorption in jejunum is about 2 times faster than that in ileum. the reason is that the increased ionization in ileum leads to a decrease in Pm value and, consequently, to reduced permeability coefficient PC

Back 52

true