Lecture No. 4.

PHARMACOKINETICS – mechanism of drug transport processes

LECTURE NO. 4
1. The pharmacological action/effects depend upon concentration of
drugs at the target tissue.
2. The time-course of a drug’s action generally reflects time course of the rise
and fall of its concentration at the target tissue.
3. Exception to this are the drugs – ‘Hit and run drugs’, which act irreversibly
or almost so and their effect remains when the concentration has dropped to
zero, e.g.
i) Drugs which kill cells or render them incapable of division
ii) Drugs which inactivate an enzyme or receptor irreversible.
4. The concentration of any drug at any point of time after its administration in
the body depends upon two processes.
i) Translocation of drug molecules: Movement of molecules to different
parts of the body from its site of drug administration. It comprises of
absorption, distribution & excretion.
ii) Chemical transformation of drug molecules or Biotransformation of drug
molecules: results in formation or disappearance of active drug
molecules.
Translocation of drug molecules
It occurs by:
1. By bulk flow transfer (i.e. in the blood stream) – it provides very
fast long distance distribution system for all solutes irrespective of their
chemical nature.
2. By diffusional transfer (i.e. molecule by molecule transfer or short distance
transfer) – Here.
i) The transfer of drug molecules occurs across cell membrane barriers that
separates the various aqueous compartments of the body i.e.
Plasma water (5%)……………………B F

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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

Interstitial water (16%)……………….B F

Intracellular water (35%)……………..B F

Transcellular water (2%)………………B F

Fat (20%) ……………… F

ii) The drug is present in bound and free form in these compartments except
fats (where the drug is in free form).
iii) The free form of drug is able to move between compartments and its
movement and availability at the site of action depends upon
a) Molecular size and shape
b) Degree of ionization
c) Relative lipid solubility of its ionized and nonionized forms.
d) Binding to serum/tissue proteins.
iv) In most cases, the drug may have to traverse the plasma membrane of many
cells to reach to its site of action.
Structure of Cell membrane:
1. Bilayer of amphipathic lipids i.e. contains both hydrophilic and
hydrophobic portions. The hydrophilic heads are oriented outwards and
hydrophobic hydrocarbon chains oriented inwards to the centre of the
bilayer to form a continuous hydrophobic phase.
2. Individual lipid molecule in the bilayer moves laterally and can organize
with cholesterol molecule and provide fluidity, flexibility, organization,
high electrical resistance and relative impermeability to highly polar
molecules.
3. Membrane protein embedded in the lipid bilayer serve as receptor, ion
channels or transporters to transduce electrical or chemical signaling
pathways and provides selective targets for drug action.

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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

Transport across cell membranes: Cell membrane constitutes barriers between

aqueous compartments. These can be of various types.
1. Single layer thick - separates intracellular from extracellular
compartment.
2. Two layer thick - e.g. epithelial barriers of GI mucosa and renal tubules.
3. Endothelial barrier -These are gaps between endothelial cells of
capillaries and permit small molecules (<30,000 mol. Wt) to cross by
aqueous diffusion. Therefore, most protein molecules cannot cross.
4. Blood brain barrier- The capillary endothelium is continuous and tightly
packed and no gaps in between, therefore, bulk flow of water can carry
with it small water soluble substances lesser than molecular mass of 100-
200 da. The larger lipophilic drugs must pass through the cell membrane
itself.

Ways/mechanism of drug transport:

Broadly of two types Simple transport
Facilitated transport
Simple transfer: Drug moves from higher concentration to lower concentration.
Further of two types:
a) Passive membrane transport or simple diffusion or passive diffusion
b) Filtration
Facilitated transport: Drug transport is facilitated by net expenditure of
energy or with a carrier molecule or both. Further of three types.
c) Active transport
d) Facilitated diffusion
e) Pinocytosis
a) Passive membrane transport: Most important mean of drug transport
across biological membrane. Here the drug molecules usually penetrate by

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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

diffusion along a concentration gradient or downhill movement by virtue of its

solubility in lipid bilayer.
- It occurs without expenditure of energy.
- Both nonpolar lipid soluble compounds and polar water soluble substances
that possess sufficient lipid solubility can be diffused.
- The drug present in aqueous medium at one end of the biological membrane
partitions & gets dissolved in the lipid phase of the membrane and finally
leaves it by dissolving again in aqueous medium at the other side of the
membrane.
- The rate of transfer of a drug across a biological membrane by passive
diffusion (J) is determined by Fick’s Law of diffusion.
J= k. Δ C where, k = D.A. P/T

ΔC = (C1 – C2)
D: The diffusion coeff. of a drug. Nonpolar (nonionized) drugs are
expected diffuse quickly through lipid & aqueous membranerane.
A: The surface area of the organ in which transport is occurring.
Larger the surface area faster will be diffusion.
P: Partition coeff. – relates movement of drug from drug product to
biological membrane
Δ C or (C1 – C2): denotes difference in the concentration of the drug on
either side of membrane
T: thickness of the membrane thicker the membrane lesser will be the
transfer.
- For an effective diffusion, the drug should be soluble in lipid phase and
aqueous phase i.e. a perfect lipophilic – hydrophilic balance (LHB) should
be there.
* Highly hydrophilic drugs are poorly diffusible because of their inability to
cross lipid membrane.

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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

* Extremely lipid soluble drugs are poorly diffusible because they are totally
insoluble in aqueous body fluids and so cannot gain access to surface of cell.
- Once the steady state is achieved the concentration of the unbound drug is
same on both side of the membrane if the drug is nonelectrolyte.
For ionic compounds, the steady state concentration depends upon the
electrochemical gradient of unionized fraction and on differences in pH across
the membrane which may influence the degree of ionization of molecule. This
can be explained by the pH - partition hypothesis.
Most of the drugs are weak acids or bases that are present in solution as
ionized and nonionized species.
Drugs in nonionized form can difuse across the cell membrane as they are
more lipid soluble. The degree of ionization depends upon the pKa of the drug
and pH gradient across the membrane. The pKa of a drug is the pH at which
half the drug is in ionized form. pKa is the negative logarithm of dissociation
constant.
The relative amount of ionized and unionized drug in the body fluid at a
particular pH and the per cent of drug ionized at this pH can be determined by
Handerson-Hasselbalch equation.
For weak acidic drugs:
pKa – pH = log [concentration of unionized drug/ concentration of
ionized drug]

% Ionized drug = 100

1+antilog (pKa – pH)
For a weak acidic drug, say Ibuprofen, pKa = 4.4 its ionization at a pH 4.4 will
be
4.4 – 4.4 = log [concentration of unionized drug /
concentration of ionized drug
0 = Log [U] / [I]
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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

Taking antilog of both sides

1 = [U] / [I] [U] = 50% & [I] = 50%

At a pH 1.4, (gastric acid pH)

4.4 – 1.4 = Log [U] / [I] or 3 = Log [U] / [I]

Taking antilog
1000 = [U] / [I] If (U) = 1 then [I] = 0.001

At pH 7.4 of plasma
4.4 – 7.4 = Log [U] / [I] or -3.0 = Log [U] / [I]
Taking antilog
0.001 = [U] / [I] i.e [U] = 0.001 and [I] = 1
Or If [U] =1 then [I] = 1000
For acidic drugs, when the pH of environment is lesser than pKa then unionized
fraction is more than ionized fraction and more absorption occurs.
For weak basic drugs:
say quinidine (pKa = 4.4)
pH – pKa = Log [U] / [I]
At gastric pH, 1.4
1.4 – 4.4 = Log [U] / [I] or -3 = Log [U] / [I]

Taking antilog,
0.001 = [U] / [I] or [U] = 1 and [I] = 1000
At pH 6.4 of intestine
6.4 - 4.4 = log [U] / [I] or 2.0 = log [U] / [I]
100 = [U] / [I] or unionized = 100 and ionized = 1

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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

For weak basic drugs, when pH of environment is more than its pKa value then
unionized fraction is more and hence absorption of such drugs is more in
intestines than stomach.
b) Filtration:
- Passage of drugs through aqueous pores/channels is called as filtration. Very
small particles (Mol. Size <100) or polar and nonpolar substance are filtered
alongwith bulk flow of water occurring due to hydrostatic pressure or
osmotic differences.
- It is not structure specific, not energy dependent and occurs down to
concentration gradient.
- Filtration is important mode of drug transfer in:
i) Capillary endothelial cells (except those in brain) which are separated by
slits that serves as pores and are nearly 40A o size. Many large molecules can
filter through them.
ii) Renal excretion (glomerular filtration) of drugs
iii) Removal of drugs from CSF
iv) Passage of drugs across hepatic sinusoidal membrane
c) Active transport:
- Active transport is energy dependent and carrier mediated i.e. transport
across the membrane barrier takes place with the help of a carrier
molecule and a net energy is utilized in this process as the movement of
molecule occurs across the concentration or electrochemical gradient i.e.
from lower concentration to higher concentration or up-hill movement.
The energy is also utilized for the energization of carrier molecule.
- Carrier molecule combine with drug/solute and a complex is formed. This
complex then traverses across the membrane barrier, where it discharges
the solute molecule and return to its original site to carry afresh molecule.
- This process is structure specific i.e. carriers possess special affinity for and
transport drugs of specific chemical structures only.
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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

- The no. of carriers are limited and a no. of essential nutrients like Na +, K+,
glucose, aa and vitamins are transported, therefore, it generally get
saturated.
- Drugs of similar structure compete for a particular carrier molecule.
- It is imp. mode of transport for hydrophilic, large polar or electrolyte
substances and drugs having structural similarity to endogenous
substances
e.g. 5-fluorouracil and 5-bromouracil.
Types of active transport:
a) Primary active transport:
Only one substance is carried by the carrier molecule against its
concentration gradient.
b) Secondary active transport:
Two substrates are carried by a carrier molecule. One is driving solute (Na +,
K+ or Ca+2) which is transported along its concentration gradient and the
other is actual substrate which is transported against its concentration
gradient.
i) When the direction of transport of driving solute and actual substrate is same
the process is called cotransport or symport. eg. Na + cotransport of glucose
or a.a. in GIT mucosa.
ii) When the direction of transport of the two is opposite then the process is
called counter transport or antiport. e.g. Na+ counter transport of H+ions.
d) Facilitated diffusion:
It is a carrier mediated passive transport that operates along the
concentration gradient (down hill movement)
- Since the driving force is concentration gradient so it does not require
energy.
- proceeds more rapidly then simple diffusion and can translocate non
diffusible substances.
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Lecture No. 4. PHARMACOKINETICS – mechanism of drug transport processes

- Structure specific and saturable process like active transport and is subject
to competition between agents having similar structures.
- It is not a major mode of drug transport e.g. Glucose transport in R.B.C.s,
Intestinal absorption of Vit B1 & B2.
e) Pinocytosis: It operates for agents having molecular mass more than 1000
da.
- involves engulfing extracellular materials within a segment of the cell
membrane to form saccules or vesicles.
- Vesicles are pinched off intracellularly and release the engulfed particles.
- Like active transport, it also requires energy, shows low order structure
selectivity and is a competitive and saturable process.
- It operates for uptake of macromolecular nutrients like fats, starch, proteins,
fat soluble vitamins (A,D,E & K) and drugs as insulin and poliovaccine
- It contributes little to transport of most drugs.
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