ADME 1

Drug passage through biological

membranes
MEDSCI 303
Lecture 4

James W. Paxton
Dept of Pharmacology & Clin Pharmacology

Learning Objectives
To describe the various mechanisms of drug
passage through biological membranes
To understand the major factors involved in
passive drug diffusion
To apply the Henderson-Hasselbalch equation
to calculate % non-ionized, drug pKa, and pH of
a solution.

Lecture Outline
Mechanisms

of drug passage through

biological membranes
Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis
Filtration (?)

Drugs

as weak electrolytes

pKa pH = Log [AH]

[ A -]
pKa pH = Log [BH+]
[B]

(acid drug )
(basic drug )

Summary of drug disposition in the body

Drug dosage
Metabolism
liver or extrahepatic

Binding to
plasma proteins
(albumin)

Metabolites
Free drug concentration
in extracellular
water

Binding and
storage in tissues

inactive or active

Biliary excretion
enterohepatic recirculation

Renal excretion

(protein, fat)

Drug conc at site of action

glomerular filtration
tubular secretion
passive reabsorption

Receptor occupancy
Intensity of pharmacological effect

Main mechanisms of transport

across biological membranes :
5

e.g., Epithelial cells of GI tract

Drug

ADP
ATP

Lymph

Blood

Lymph

Transcellular diffusion

Drug

Active transport

Drug

Drug

Facilitated diffusion

Endocytosis

Passive diffusion :
Most

important mechanism
Applies to non-polar drugs
(ie, lipid/oil/fat soluble)
Conc

gradient is the driving force

No energy required

Rate of passive diffusion

depends on :

Concentration

gradient (C1 C2)

Surface area (A)
Thickness of membrane (d)
Diffusion coefficient of the molecule (D)
Rate of diffusion (R) = (C1 C2) x A x D
d
If C2 << C1, then R = C1 x constant, (i.e. AD/d)
Rate of diffusion is proportional to conc at the diffusion site
a first-order reaction rate

What is a partition coefficient ?

If drug is added to an oil/water mixture and allowed to

equilibrate, drug concentrations in oil and water phases
can be expressed as a ratio.
Partition Coefficients

Note: roughly equivalent pKa values,

so degree of ionization similar for all 3 drugs.
(Human Pharmacology, 3rd Edn, 1998; Eds Brodie, Larner & Minneman)

Ionization and pH

Most

drugs are weak acids or bases, and ionize

in solution.

Weak

acids give up a H+ (proton) and become

negatively charged.
Weak acids become more ionized as pH
increases (more alkaline).
Weak

bases ionize by accepting a H+

Weak bases become more ionized as pH
decreases (more acidic).
Ionized

drugs are not very lipid soluble

10

Only the nonionized (uncharged) form of

a drug will readily cross cell membranes
(HA or B)

Cell

(A- or HB+)

11

Most drugs ionize in solution and an equilibrium is

reached between fraction ionized & non-ionized :
e.g. an acid

HA D A- + H+

Law of Mass Action

Rate of a reaction conc of active masses
Thus at equilibrium :

[ A- ] [ H + ]
[ HA]

= Ka

(Association
constant)

This mass action equation can be more conveniently

expressed in terms of pH and pKa;
pH is the negative log of H+ conc, i.e. 10-7 M = 7
pKa is the negative log of the Association Constant

12

[ A- ] [ H + ]
[ HA]

= Ka

Log [H+] + Log [A-] Log [HA] = Log [Ka]

- (-Log [H+]) Log [Ka] = Log [HA] - Log [A-]
pKa pH = Log [AH]
[ A -]
pKa pH = Log [BH+]
[B]

(acid drug )
(basic drug )

pKa pH = Log [protonated/unprotonated]

The Henderson Hasselbalch equation

13

If we put a drug with a pKa = 7.4 into a

solution with pH 7.4; by applying the
Henderson-Hasselbalch equation:
pKa pH = Log [AH]
[ A -]
but antilog of 0 = 1

0 = Log [AH]
[ A -]
1 = [AH]/ [A-] = 1/1

i.e., equal concs of ionized and nonionized

or 50% of each
Thus the pKa of a drug is the pH at which the drug
is 50% ionized

14

So what ? Is it important ?
Biological

fluids (blood, stomach and intestines, urine)

have different pHs
Can affect how and where drug is absorbed and how well

excreted in urine

The

Henderson-Hasselbalch equation can be used to

calculate how much drug crosses a membrane, if we
know:
Whether the drug is a weak acid or base
Its pKa
The pH of the environment

15

Effect of pH on the ionization of benzoic

acid (pKa = 4) & aniline (pKa = 5)
pH
1

Benzoic
acid
COOH

%
nonionized
99.9

Aniline
NH3+

%
nonionized
0.01

99

0.1

90

50

10

COO-

NH2

10

50

90

0.1

99

16

EFFECT OF pH ON INTESTINAL ABSORPTION IN

THE ISOLATED RAT SMALL INTESTINE
pKa
Acids
5-nitrosalicylic
salicylic
acetylsalicylic
benzoic

% absorbed at
pH 4 pH 5 pH 7 pH 8

2.3
3.0
3.5
4.2

40
64
41
62

27
35
27
36

Bases
aniline
aminopyrine
quinine

4.6
5.0
8.4

40
21
9

48
35
11

0
30
0
35
58
48
41

0
10
0
5
61
52
54

Data from: Schanker LS, J Pharmacol Exp Ther 123:81, 1958.

17

Distribution of weak acid and

basic drugs into breast milk :
Membrane barrier

Breast milk
(pH 7.0)

Plasma
(pH 7.4)

ionised

ionised

nonionised

nonionised

nonionised

nonionised

ionised

ionised

Weak bases breast milk

being more acid, tends to
collect drugs which are
weak bases

Weak acids as plasma is

more alkaline, drugs which
are weak acids are less
concentrated in breast milk

18

Drug diffusion into breast milk ?

Calculate the milk/plasma concentration ratio for a weak
base, pKa = 7.4 in plasma pH 7.4 and breast milk pH 6.4
Plasma pH = 7.4
pKa pH = Log [BH+]
[B]

[1]

BH+

Milk pH = 6.4
BH+ [ 10 ]

7.4 6.4 = Log [BH+]

[B]
1 = Log [BH+]
[B]

[1]

[1]

10 = [BH+]
[B]

The milk/plasma conc ratio

= (10 + 1) / (1 + 1)
= 11 / 2
milk conc is 5.5 x plasma conc

19

breast milk
serum

Concentration-time profile for a weak base, cimetidine in

serum (l) and breast milk (O) after a single dose in a
lactating female. Reproduced from Clin Pharmacol Ther 58:548-555, 1995.