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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5722_Библиотеки_им_академика_М_И_Перельмана.pdf
Biopharmaceutics
59
All the aforesaid variants pertaining to the ‘principal mechanisms’ shall now be treated individually in
the sections that follow.
6.1. Passive Diffusion
Passive diffusion relates to the movement of drug molecules from a region of higher concentration to a
region of lower concentration via a membrane that does not participate in the actual process. However,
it may be expressed quantitatively by Fick’s fi rst law of diffusion.
In other words, this typical phenomenon is exclusively ‘passive’ since no external energy is expended
virtually. It may be observed explicitly that the drug molecules do exhibit a tendency to move randomly
forward and backward specifi cally across a membrane as illustrated vividly in Figure 2.14.
In actual practice, two typical situations may arise distinctively as follows:
1. Two Regions Having Same Drug Concentration: Here, the forward-moving drug entities
shall be balanced by molecules moving backward, thereby giving rise to absolutely little overall net
transfer of drug.
2. A Region Having Higher Drug Concentration vis-à-vis Other Region: In this instance, the
actual number of the forward-moving drug molecules shall be higher than the number of backward-
moving drug molecules, thereby resulting in an obvious glaring transfer of molecules to the particular
region having the critical lower-drug concentration, as shown by the ‘big-arrow’ in Figure 2.14.
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Figure 2.14 Diagrammatic representation of passive diffusion of drug molecules.
The various essential aspects essentially comprise the following:
1. Drug molecules in solution have a tendency to diffuse randomly in all directions equally
and squarely.
2. Since the drug molecules undergo diffusion from LHS to RHS and vice versa (as indicated by
small arrows in Figure 2.14), one may evidently visualize and observe an overall net diffusion
taking place from the high-concentration region to the low-concentration region perceptively.
3. The aforesaid sequence of fateful event results in a net ‘fl ux’,
43
designated as J, to the RHS.
In fact, the resulting ‘fl ux’ is duly measured in mass per unit area (viz. mg cm
−2
).
44
Explanation
43
Flux: It refers to the rate of drug transfer and is usually represented by a vector to indicate its actual direction.
44
Shargel L and Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 4th edn., McGraw-Hill Medical Publishing,
New York, 1999.
Essentials of Biopharmaceutics and Pharmacokinetics
60
6.1.1. Fick’s Law of Diffusion
It has been duly established that a majority of drug molecules obviously undergo ‘passive diffusion’ via
the most common and major transmembrane phenomenon. Nevertheless, the critical and main driving
force for causing the passive diffusion being the virtual difference prevailing in the drug concentrations
on both sides of the cell membrane (see Figure 2.14).
Thus, according to Fick’s law of diffusion, the drug molecules do undergo critical diffusion right
from a region of high drug concentration to the region of low drug concentration, which is given by
the following expression:
C
d
(CGI p)
d
QDAK
th
−
⎧⎫
=⋅
⎨⎬
⎩⎭
where
dQ/dt is the rate of drug diffusion (amount/time),
45
D is the diffusion coeffi cient of drug via the membrane (area/time),
A is the surface area of membrane for drug diffusion (area),
K is the partition coeffi cient (of the drug between the lipoidal membrane and the aqueous GI fl uids
(has no units),
h is the thickness of membrane and
CGI − Cp is the difference between the concentrations of drug in the gastrointestinal (GI) tract and in
the plasma [also know as the concentration gradient (amount/volume or mg mL
−1
)].
6.1.2. Characteristic Features of Passive Diffusion
Following are some of the characteristic features of passive diffusion:
1. Drug molecule distributes rapidly into a relatively large volume soon after gaining an access to the
circulating blood thereby resulting in an extremely low plasma-drug concentration vis-à-vis the
observed concentration at the very site of drug administration.
2. Drug substance is invariably administered in ‘mg’ doses, whereas, the recorded plasma-drug con-
centrations are often expressed as mcg mL
−1
or ng mL
−1
ranges.
3. The orally administered drugs (viz. tablets, capsules) the CGI >> Cp, which obviously indicates that
a defi nitely large concentration gradient is duly maintained and sustained thereby driving the drug
molecules very much into the plasma from the ensuing GI tract.
4. Fick’s law of diffusion obviously expatiates such cardinal aspects as
∑ lipoidal solubility of the drug molecule,
∑ surface area of the membrane and
∑ thickness of the membrane
do infl uence enormously the observed passive diffusion of drug molecules.
5. Partition coeffi cient ‘K’ evidently designates the lipid-water partitioning of a drug molecule. It may
be observed that lipid-soluble drugs (viz. steroids) do exhibit a defi nite greater ‘K’ values, which
enhance theoretically the specifi c rate of systemic drug absorption.
45
It also designates the rate of appearance of drug in the circulating blood.
Biopharmaceutics
61
6. The critical surface area of the cell membrane vis-à-vis the drug gets normally absorbed infl uences
more or less directly the actual rate of drug absorption.
7. Most drug substances get duly absorbed from several region located strategically along the GI tract.
8. Incidentally, the particular duodenal region of the small intestine clearly displays the most rapid
drug absorption perhaps under the infl uence of such obvious anatomic features as villi and micro-
villi, that distinctly afford a large surface area [see Figure 2.10(c)].
Note
In usual practice, the absorption of drug is generously infl uenced by an array of physical factors
possessed by the drug and, thus, restricts its practical application of ‘K ’.
Note
Importantly, one may not come across these villi in such a huge quantum in other regions of the
GI tract.
9. Interestingly, the cell membrane thickness ‘h’ remains constant at the very site of absorption; how-
ever, it may get changed due to certain disease conditions.
10. The capillaries are more thickly lined with the glial cells in the brain thereby creating a denser
lipid barrier [also know as blood–brain barrier (BBB)] which may cause a drug substance to undergo
diffusion in a more sluggish manner into the brain.
Note
In ‘meningitis’ (i.e., infl ammation of the membranes of the brain), the cell membranes may
become either more permeable to drug diffusion or get disrupted profusely.
6.1.3. Fate of Lipophilic and Hydrophilic Substituted Drugs
There are a good number of lipophilic and hydrophilic substituted drugs available abundantly in the
therapeutic armamentarium.
Lipophilic-substituted Drugs: Sodium salt of novobiocin, tolbutamide, testosterone palmitate;
Hydrophilic-substituted Drugs: Crystalline penicilline G, chloramphenicol succinate;
Lipid-soluble Drugs: They usually traverse across the cell membranes more easily and conveniently
than the relatively less lipid-soluble ones (more water-soluble drugs).
There are two types of drugs, namely:
1. Weak-Electrolyte Drugs [or weak acids/bases]: In this particular instance, the degree of ioni-
zation infl uences
∑ solubility of drug and
∑ rate of drug transport.
2. Ionized Drugs: Mostly the ionized drugs (or polar drugs) are found to be more water-soluble
vis-à-vis the non-ionized drugs that are more lipid soluble in nature.
Essentials of Biopharmaceutics and Pharmacokinetics
62
It is, however, pertinent to mention here that the degree of ionization of a ‘weak electrolyte’ [see
(1) above] solely depends upon
∑ pK
a
value of the drug substance and
∑ pH (i.e., partition hypothesis) of the medium where the ‘drug’ remains in a dissolved state.
6.1.4. Implication of Henderson and Hasselbalch Equation
According to the Henderson and Hasselbalch equation, the prevailing ratio of charged state of drug to
uncharged form of the drug depends exclusively upon the following factors, such as:
∑ pH conditions and
∑ pK
a
value of ‘drug substance’.
Thus, we may have two different ratios for ‘weak acids’ and ‘weak bases’ as given under:
For ‘Weak Acids’:
()
()
()
a
pH p
Salt
[A ]
Ratio 10
Acid HA
K
−
−
===
For ‘Weak Bases’:
a
(pH p )
+3
Ratio ( Base)(Salt) [RNH]2 [RNH ] 10
K−
=− = =
Following are two typical examples to exemplify the weak acids and weak bases:
1. Salicylic Acid (i.e., a ‘Weak Acid’): As per the inherent pH of salicylic acid, it is expected
to get absorbed readily right from the stomach (pH 1.2) by virtue of a congenial and favour-
able existence of a concentration gradient of the unionized (i.e., more lipid-soluble) state of
the drug from the stomach into the circulating blood.
46
2. Quinidine (i.e., a ‘Weak Base’): The drug gets highly ionized in an environment of
acidic pH and gets absorbed rather sluggishly right from the stomach. Importantly, majority
of drugs are duly governed by the prevailing pH; however, in actual practice most of the
drugs get abundantly absorbed in the duodenum
47
perhaps due to the availability of a rela-
tively large and extended surface area plus a high blood-fl ow.
Examples
6.2. Pore Transport (Convective Transport)
Pore transport (or convective transport) refers to the smooth passage of large molecules or small particulate
colloids via a minute opening in a cell membrane tissue (serving as a fi ltration membrane). It is also
known as a bulk fl ow or simply fi ltration.
46
This is on account of the fact that almost ‘all the drug’ present duly in the blood compartment get entirely ionized
(or dissociated) at pH 7.4.
47
That is, small intestine.
Biopharmaceutics
63
Importantly, pore transport predominantly aids in the following three critical and specifi c drug vari-
ants, namely:
∑ low molecular weight drugs (with values < 100),
∑ low molecular size drug (having lesser diameter than the pore itself ) and
∑ usually water-soluble drugs via narrow aqueous-fi lled channels or membranes duly present in the
membranes structure.
The three most common components are urea, carbohydrates and water.
Examples
6.2.1. Highlights of Pore Transport
These essentially consist of
1. Linear or chain-like drug molecules having molecular weight up to 400 Da and may also get
absorbed by fi ltration.
2. In true sense, the driving force is meticulously caused by two physical characteristic features, namely:
∑ hydrostatic pressure or
∑ osmotic differences,
prevailing across the membrane on account of which the bulk fl ow of water along with small solid
molecules comes into being via such aqueous channels.
Water Flux: Water fl ux normally refers to the excessive fl ow or discharge of water across a mem-
brane. It promotes prominently via the aqueous channels and is frequently termed ‘solvent drag’.
The specifi c importance and advantageous benefi ts due to the ‘drug permeation’ via the water-fi lled
channels are as stated under:
∑ renal excretion,
∑ critical removal of ‘drug’ from the cerebrospinal fl uid (CSF) and
∑ access of ‘drug substances’ into the liver.
6.3. Carrier-Mediated Transport
On the basis of theoretical grounds, one may take cognizance of the underlying fact that a lipophilic
drug substance would be able to pass via the cell or even go around it. Importantly, in case, a drug pos-
sesses a low molecular weight and also is lipophilic in nature, it may be safely noted that the ensuring
lipid-cell membrane fails to pose as a stiff barrier to
∑ drug diffusion and
∑ drug absorption.
Interestingly, in the entire length of the small intestine, such drug molecules that are smaller than 500 MW
would get absorbed particularly by the so-called ‘paracellular drug absorption’.
In other words, there exists a host of ‘polar drugs’ or ‘ionized drugs’ that do have a tendency to cross
the cell membrane more rapidly vis-à-vis based on the prediction from their respective inherent:
∑ concentration gradient values and
∑ partition coeffi cient values.
Essentials of Biopharmaceutics and Pharmacokinetics
64
In a broader perspective, the aforesaid concepts and ideas suggest overwhelmingly the prominent and
critical presence of certain highly specialized ‘transport mechanisms’ without which an array of water-
soluble essential nutrients, e.g., vitamins, amino acids and monosaccharide (glucose), shall undergo absorp-
tion rather slowly and sluggishly. The most preferred and logical mechanism that explains the above may be
the specifi c component of the membrane invariably termed as the ‘carrier’ which gets duly bound
∑ reversibly and/or
∑ noncovalently,
in association with the solute molecules (e.g., drug molecules) intended to be transported ultimately.
It has been observed with enough evidential support that the emerging carrier–solute complex does
traverse very much across the membrane to the other side, where it eventually dissociates and discharges
the intended drug molecule. After playing its pivotal role, the ‘carrier’ gets back to its so-called ‘original
site’ so as to go ahead with the completion of the cycle by promptly accepting another fresh/new drug
molecule of the solute. Interestingly, the said ‘carrier’ could be critically
∑ an enzyme or
∑ certain other integral constituent belonging to the membrane.
6.3.1. Important Characteristic Features of Carrier-Mediated Transport
Following are the fi ve vital and important characteristic features of the carrier-mediated transport, namely:
1. Importantly, the critical ‘transport process’ turns out to be highly structure specifi c, which means
that the ensuring carriers do possess not only a special affi nity for, but also has the ability to transfer
a ‘drug’ with a particular chemical structure only. In general, the carriers exhibit a special affi nity
for certain essential nutrients.
2. As the carrier-mediated transport system happens to be a structure-specifi c one, such drug substances
having a close structural resemblance to the essential nutrients (viz. amino acids, glucose, vitamins
etc.) invariably termed as the ‘false nutrients’ are adequately absorbed by the same carrier system.
Several anti-neoplastic drugs, e.g., 5-fl uoracial [or 5-FU], 5-bromouracil [or 5-BU], do serve as
false nutrients, thereby indicating the importance of their mechanism of action.
Example
3. Since the exact and precise number of carriers is usually restricted, the transport system is invari-
ably subjected to encounter a sort of competition between such drug molecules possessing inti-
mately identical structures.
4. Furthermore, as the actual number of carriers is found to be limited in quantum, the transport system
is regarded to be a capacity-limited system. In other words, at higher level of drug concentration, the
aforesaid system is rendered almost saturated; and therefore, ultimately approaches an asymptomatic
state. Nevertheless, it is important to note that for a drug substance being suitably absorbed by
∑ passive diffusion processes—where by the rate of absorption gets enhanced linearly with the
ensuring concentration of ‘drug’ and
∑ carrier-mediated processes—whereby the absorption of the ‘drug’ increases almost linearly with its
concentration till such time the resulting carriers get duly saturated after which it is rendered
_ curvilinear and
_ accomplishes a ‘constant value’ at specifi c higher dose levels.
Biopharmaceutics
65
Figure 2.15 illustrates the typical comparison in the actual rate of absorption vis-à-vis the drug concen-
tration plots duly obtained for
∑ passive diffusion transport process and
∑ carrier-mediated transport process.
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Figure 2.15 A typical comparison between the actual rate of absorption of drug vs. drug concentration plots
due to passive diffusion and carrier-mediated transport processes.
Various steps essentially include:
1. A capacity-limited process may be expatiated duly by means of the mixed-order kinetics,
which is also known as non-linear kinetics or Michaelis–Menten saturation.
2. The phenomenon is termed as ‘mixed-order kinetics’ by virtue of the following two glaring
facts:
∑ It remains fi rst-order at the sub-saturation drug concentration levels exclusively.
∑ It attains zero-order at as well as above saturation levels ultimately.
3. Besides, the ensuring capacity-limited specialized features of such a system do suggest that
the observed bioavailability of a drug substance being absorbed meticulously via such a sys-
tem retard with an increasing dosage regimen.
Explanations
A typical example includes administration of water-soluble vitamin, e.g., vitamins B
1
, B
2
and B
12
.
Example
Note
Therefore, the administration of a ‘single large oral dose’ of the vitamins B
1
, B
2
and B
12
appear to
be absolutely irrational and uncalled for.
Essentials of Biopharmaceutics and Pharmacokinetics
66
5. The carrier-mediated absorption process (or specialized absorption phenomenon) invariably comes
into play from the specifi c sites located strategically in the intestinal tract that are found to be
abundantly richer in the availability of requisite carriers.
Concept of Absorption Window: It refers to ‘an area wherein the particular carrier-system is
observed to be highly dense’.
Incidentally, all drugs that are duly absorbed via these types of absorption windows do represent as
poor candidates (drugs) usually required for the controlled-release formulations.
6.4. Active Transport
The ‘active transport’ may be defi ned as ‘the process by which a cell membrane moves molecules against
a concentration or electrochemical gradient.’
It is indeed a metabolic work. A glaring example being the very low observed concentration of K
+
ions present in the extracellular fl uid (ECF). Besides, there are other ions that are transported actively,
e.g., Na
+
, Ca
2+
, H
+
, Fe
2+
, Cl
−
, I
−
and H
2
NCONH
3
+
(urate). Interestingly, there are quite a few amino acids
and carbohydrates that also transport actively.
Another school of thought believes that ‘active transport’ is more or less a carrier-mediated trans-
membrane process which is found to be absolutely essential for
∑ GI absorptions of certain drug substances and
∑ active participation in both renal and biliary secretion of several drug molecules and their respective
metabolites.
Mechanism of Action: The mechanism of active transport may be explained judiciously when a carrier
binds the drug molecule to give rise to the formation of a carrier–drug complex which carefully carries out
the following two activities, namely:
∑ pushing the drug across the membrane and
∑ subsequent dissociation of the drug on the other side of the membrane as depicted in Figure 2.16(a)
and (b).
Figure 2.16(a) and (b) clearly explains the following related aspects pertaining to the ‘active transport’,
such as:
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Figure 2.16(a) Representation of a hypothetical carrier-mediated transport phenomenon.
(Adapted from: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 4th edn. New York: McGraw Hill Medical
Publishing, 1999.)
Biopharmaceutics
67
∑ Candidate ‘drug’ is duly transported from a region of lower concentration to a region of higher
concentration, i.e., a sort of ‘uphill transport’ or sometimes also referred to as ‘against a concentration
gradient’, without attaining a state of equilibrium.
∑ As the ensuring phenomenon engages a ‘uphill transport’, it essentially needs energy for the neces-
sary-job-done by the carrier.
∑ Since the entire phenomenon requires prominently the critical utilization of energy, it may be inhib-
ited duly by the incorporation of certain ‘metabolic poisons’, viz. lack of O
2
, F, CN
−
and dinitroph-
enol, which directly interfere with the vital function of energy production.
6.5. Facilitated Diffusion
The facilitated diffusion may be defi ned as ‘the movement of molecules (drugs) across a membrane bar-
rier in which a carrier protein is required’.
It essentially involves the movement of drug molecules from a region of higher concentration to a region
of lower concentration, and the most entrusted driving force being the concentration gradient. Besides, no
other energy input is ever required beyond that necessary for carrying out the normal cellular function.
In short, the ‘facilitated diffusion’ designates predominantly
∑ a non-energy needed transport system and
∑ a carrier-mediated transport system,
wherein the ‘drug substance’ moves critically and essentially very much along a concentration gradient.
Facilitated diffusion does possess the following three major characteristic features, namely:
∑ process entails a ‘saturable one’,
∑ remains selective structurally for ‘drug entity’ and
∑ exhibits distinct ‘competition kinetics’ for drugs having a similar structure.
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Figure 2.16(b) Diagrammatic representation of an active absorption of a drug (ATP = adenosinetriphosphate).
Note
Generally, the facilitated diffusion plays a rather not-so-important role in the entire phenomenon
related to the absorption of drug molecule.
(Adapted from: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 4th edn. New York: McGraw Hill Medical
Publishing, 1999.)
Essentials of Biopharmaceutics and Pharmacokinetics
68
Figure 2.17 depicts the diagrammatic representation of the facilitated diffusion of vitamin B
12
(cyanocobalamine).
6.6. Carrier-Mediated Intestinal Transport
It has been duly observed that there exists a plethora of carrier-mediated systems (transporters) located
strategically at
∑ intestinal brush border and
∑ basolateral membrane
serving specifi cally for the critical absorption of certain specialized ions and nutrients required urgently
for the human body. An array of drug substances get absorbed meticulously by the aid of these carriers
due to their close structural similarity to the naturally occurring substrates.
Some typical examples engaging essentially such a remarkable transport system comprise:
1. Entry of ‘glucose’ into the RBCs,
2. Intestinal absorption of water-soluble vitamins B
1
and B
2
. Nevertheless, one may expatiate
the probable mechanism with respect to the passive facilitated diffusion in the GI absorption
of vitamin B
12
. Thus, an intrinsic factor (IF), and a critical glycoprotein generated duly by
the gastric parietal cells, ultimately gives rise to the formation of a complex with vitamin B
12
(cyanocobalamine), that eventually is transported across the so-called ‘intestinal membrane’
with the help of a carrier system.
Examples
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Figure 2.17 Diagrammatic representation of facilitated diffusion of vitamin B
12
.