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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
Biopharmaceutics
39
3. The genuine attempt for targeting a polar drug (or ionized drug) directly into the brain, in some
serious and acute conditions, viz. cancerous tumour in the brain, had always been a matter of deep
concern in the medical profession. The advent of scientifi c advancement in the past few decades
have actually introduced three different and important approaches that virtually enabled the suc-
cessful utilization to induct drug(s) across the BBB, namely:
(a) Permeation enhancers, i.e., dimethysulfoxide (DMSO), in conjunction with the drug substance.
(b) Osmotic imbalance of BBB, i.e., to disrupt/imbalance the ensuing osmotic pressure across the
membranes (BBB) by carrying out the careful infusion of the carotid artery with mannitol
solution.
(c) Drug carrier, i.e., adaptation of dihydropyridine redox system, as a drug carrier to the brain.
Mechanism of Dihydropyridine: In this particular instance, dihydropyridine (a lipid-soluble com-
pound) gets intimately hooked on as a perspective ‘carrier’ to the polar drug (or ionized drug) to give
rise to the formation of a ‘prodrug’ which crosses the BBB rapidly. Importantly, in the brain the pres-
ence of distinct CNS-enzymes helps in the critical oxidation of the ensuing dihydropyridine molecule
to the corresponding polar pyridinium ion
1+
⊕
state that may not be able to escape out of the brain
anymore. Consequently, the ‘drugmolecule’ gets eventually trapped into the brain.
18
Parkinsonism: It refers to a group of neurological disorders characterized by tremour, hypokinesia and rigidity.
19
Choroid plexus: It refers to the dark blue vascular layer of the type between the selera and retina, extending
duly to the optic nerve.
Parkinsonism
18
may be treated effectively by ‘levodopa’(a prodrug) that can penetrate CNS to get
converted to dopamine via metabolism.
Example
Note
The aforesaid dihydropyridine-redox system has been gainfully employed in the effective release/
delivery of ‘steroidal drugs’ right into the brain.
4.4. Blood–Cerebrospinal Fluid Barrier (BCSFB)
The cerebrospinal fl uid (CSF) is generated in the choroid plexus,
19
specifi cally at the lateral, third and
fourth ventricles. However, it is similar in composition to the extracellular fl uid (ECF) of the brain. It has
been duly observed that the strategically located capillary endothelium that critically lines the choroid
plexus do have several open gaps (or junctions) through which the drug substances may fl ow without
any hinderance (i.e., freely) right into the extracellular space prevailing between the
∑ capillary walls and
∑ choroidal cells.
Nevertheless, the choroidal cells are joined meticulously to one another by means of the tight junctions
that crucially give rise to the formation of the said blood–CSF barrier that predominantly exhibits the
permeability characteristics features very much akin to the blood–brain barrier (BBB) (see Figure 2.4).
Essentials of Biopharmaceutics and Pharmacokinetics
40
However, Figure 2.5 illustrates the blood–cerebrospinal fl uid barrier (BCSFB) through which the
transport of the lipid soluble drug takes place.
Modus Operandi: As one may observe in the particular instance of BBB, the highly lipid soluble drugs
would sail across the BCSFB without any obstruction, whereas, the corresponding moderately lipid sol-
uble drugs and partially ionized drug entities permeate rather sluggishly and slowly. Obviously, a specifi c
drug substance that enters the CSF gradually would never accomplish a distinctly high concentration
due to the fact that the usual ‘bulk fl ow of cerebrospinal fl uid (CSF)’ will remove continuously the ‘drug
substance’ from the circulating blood. Importantly, at any point in time, any administered ‘drug substance’
shall explicitly show its concentration in the brain invariably at a higher level vis-à-vis in the CSF.
Mechanism of Action: Evidently, the precise mechanism pertaining to the critical diffusion of
drugs right into the CNS and CSF are almost at par with each other. However, the extent of drug uptake
may vary appreciably.
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Figure 2.5 Diagrammatic representation of the transport of lipid solute drug across blood–cerebrospinal fl uid
barrier.
Following are some typical examples:
1. Sulphamethoxazole and Trimethoprim (Septran
®
): This specifi c drug combination
(used as anti-bacterial agent) clearly shows higher drug concentration in the cerebrospinal
fl uid (CSF) vis-à-vis its cerebral concentration.
2. Phenytoin, an anti-epileptic agent, exhibits a six-fold higher activity in epileptic patients
particularly in the temporal lobe than in the CSF.
3. β-Blockers (e.g., Timolol
®
, Propranolol
®
, Oxyprenolol
®
, Nadolol
®
, Pindolol
®
) show lower
drug concentration in the CSF.
Examples
4.5. Placental Barrier (PB)
Placental barrier (PB) is defi ned as ‘a barrier provided by the placental tissues, between the foetal and
the maternal circulation’.
Biopharmaceutics
41
It has been duly observed that the relatively small substances, excluding the blood cells, may eventu-
ally cross this barrier easily and conveniently.
It has also been established that
∑ maternal blood vessels and
∑ foetal blood vessels
are separated from each other by a good number of membrane and capillary, such as:
∑ tissue layers made up of foetal trophoblast basement membrane
20
and
∑ endothelium capillary
that eventually in combination give rise to the formation of the so-called ‘placental barrier’. Importantly,
the critical and usual fl ow of blood takes place through (a) the maternal vein and (b) the foetal vein and
arteries (blood vessels) as illustrated vividly in Figure 2.6.
Modus Operandi: Various steps essentially comprise the following:
1. The mean thickness of the ‘human placental barrier’ in the early stages of pregnancy stands at 25 μ,
which eventually gets reduced to only 2 μ in full pregnancy. Importantly, the said variance in the
thickness of human placental barrier hardly reduces its effi caciousness.
2. Several drug substances having
∑ molecular weight less than 1,000 Da, and
∑ moderate to high lipoidal solubility
actually do cross over the placental barrier almost readily by means of simple diffusion phenom-
enon, for instance:
∑ anaesthetics,
∑ antibiotics,
∑ anti-convulsants,
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Figure 2.6 Diagrammatic representation of the placental barrier (PB) and fl ow of blood across foetal
membrane.
20
Foetal Membrane: It is one of the membranous structures that protects and supports the embryo and provides
it nutrition, respiration and excretion. The structures are yolk sac, alantois, chorion, decidus and placenta.
Essentials of Biopharmaceutics and Pharmacokinetics
42
∑ barbiturates,
∑ narcotic analgesics,
∑ sulphonamides and
∑ steroids.
Note
The above observations ascertain the fact that the ‘placental barrier’ does not prove to be as effec-
tive and useful when compared to the ‘blood–brain barrier (BBB)’.
3. The essential nutrients required urgently for the normal foetal growth are adequately transported
by the specifi c and vital carrier-mediated phenomena in human body.
Immunoglobulins (Ig) needed primarily for the immuno-defensive mechanism are duly trans-
ported by the endocytosis.
21
Example
Cautions: At two critical stages, certain drugs are found to be specifi cally ‘dangerous’ in nature to the
normal growth of the foetus in humans, namely:
Stage I: During the ‘First Trimester’ when the foetal organs undergo development. Importantly, in this
particular stage, most of the drugs do exhibit their inherent and typical characteristic teratogenic effects
(i.e., serious congenital abnormalities).
Thalidomide (a banned drug), phenytoin (an anti-epileptic agent), isotretinoin (an anti-acne drug),
testosterone (a male sex hormone) and methotrexate (an anti-neoplastic agent).
Examples
Stage II: During the latter stages of pregnancy, i.e., when the drugs do show their typical known physi-
ological functions, e.g., respiratory depression caused by ‘morphine’ (a narcotic analgesic).
Note
It is, therefore, always advised to restrict heavily the usage of ‘all drugs’ during pregnancy, based
on the fact that the hazardous/adverse effects (of drug) are not known due to their uncertainty
or unpredictable physiological action in humans.
4.6. Blood–Testis Barrier (BTB)
It has been duly established that the somniferous tubules (i.e., sleep-producing tubules) are distinctly
isolated from the general circulation by a defi nite blood–testis barrier (BTB) which is regarded to be
21
Endocytosis: A method of ingestion of a foreign substance by a cell. The cell membrane invaginates to form a
space for the material and then the opening closes to trap the material inside the cell.
Biopharmaceutics
43
fairly comparable to BBB. Importantly, the BTB is strategically located not at the endothelium capillary
level but at the specifi c sertoli cell
22
junction. In fact, it is the tight intracellular junctions prevailing at
the neighbouring sertoli cells which act predominantly as the BTB.
Interestingly, the barrier (BTB) restricts prominently the free fl ow and passage of drug substances to
the following two vital and important sites, namely:
∑ spermatids and
∑ spermatocytes.
5. Factors Influencing Drug Absorption
Drug absorption may be defi ned as ‘the critical phenomenon related to movement of unchanged drug
substance from the specifi c site of administration to the systemic circulation.’
In other words, the prevailing absorption process is duly developed in the ensuing biological system
for obtaining the much required organic as well as inorganic chemicals (being utilized as nutrients) right
inside the ‘systemic circulation’ so as to maintain and sustain life.
In usual practice, the drug substances are administered orally, or injected parenterally (i.e., IV, IM, SC or
intra-arterially), whereby the drug gains entry directly into the systemic circulation and exerts the desired
pharmacologic effect(s). The extravascular administration of drugs invariably show up their therapeutic
effect only in a situation when they come in contact with the circulating blood right from very site of
application and, therefore, absorption of drugs serves as a vital and important pre-requisite step.
Nevertheless, it is rather tedious and almost diffi cult to measure exactly the concentration of drug
at such a ‘site’. Alternatively, one may, therefore, measure the actual drug concentration accurately in
plasma. Obviously, it is feasible and possible to establish a fairly acceptable correlation between the fol-
lowing two entities, namely:
∑ plasma-concentration of a drug substance and
∑ therapeutic response of the drug substance.
Figure 2.7 illustrates explicitly the following two most vital aspects, such as:
∑ quantum of drug that gains entry to the systemic circulation and
∑ rate at which the drug gets absorbed ideally.
5.1. Rate-Limited Stages in Oral Drug Absorption
It has been duly observed that a ‘drug product’ (or dosage form) undergoes the systemic drug absorption
via an array of successive rate processes, as depicted in Figure 2.8. Importantly, the solid oral immediate
release dosage forms (viz. tablet, capsule) the various rate processes involved essentially comprises the
following cardinal stages, such as:
∑ disintegration of the dosage form and subsequent release profi le of the drug,
∑ dissolution of the drug in an aqueous environment and
∑ critical absorption via the cell membranes into the systemic circulation.
22
Sertoli Cell: It refers to one of the supporting elongated cells of the somniferous tubules of the testis to which
the spermatids get attached to be nourished duly till such time they become mature spermatozoan. The sertoli
cells do produce the hormone ‘inhibin’. It is also termed as sustentacular cell.
Essentials of Biopharmaceutics and Pharmacokinetics
44
Thus, one may take cognizance of the fact that in the critical phenomenon comprising drug: disintegra-
tion, dissolution and absorption, the slowest step in the sequence signifi es the rate-determining step at
which the drug reaches the ensuing circulatory system.
Rate-limiting Step: Amazingly, in an on-going ‘kinetic process’, the slowest step is designated as
the ‘rate-limiting step’.
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Therapeutic Level
Subtherapeutic Level
Minimum Effective
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Figure 2.7 A plot between time (hrs) and plasma drug concentration exhibiting signifi cance of rate and degree
of absorption in drug therapy.
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Figure 2.8 Summary at a glance of various processes involved following oral administration of a drug in tablet/
capsule form.
(Adapted from: Blanchard J. Am. J. Pharm., 150, 132–151, 1978.)
Biopharmaceutics
45
Usually, one may come across three drug product variants, namely:
1. Controlled Release Product: In this particular instance, the observed disintegration of a solid
oral drug product is found to be more fast and rapid vis-à-vis drug dissolution and drug absorption.
2. Product with Very Poor Aqueous Solubility: In this case, the rate at which the drug gets
dissolved (i.e., undergoes dissolution) is often the slowest-observed step and, therefore, exhibits a
rate-limiting effect upon bioavailability of a drug substance.
3. Drug Product with a High Water Solubility: In this specifi c instance, the observed rate of
dissolution is fast and rapid. Besides, the rate at which the drug sails across or permeates cell mem-
branes is found to be
∑ the slowest step and
∑ designates the rate-limiting step.
5.2. Drug Absorption via Gastrointestinal Tract (GIT)
It is widely known that the ‘oral administration’ of a ‘drug’ is recognized to be the most common route
usually adopted for systemically acting drug substances. Perhaps, therefore, one would expect to lay more
emphasis on the gastrointestinal (GI) absorption of drugs. Besides, it essentially embraces almost a broad
spectrum of the so-called observed drug absorption variability.
In order to understand the in-depth intricacies of the various aspects of GI-drug absorptions, it will
be worthwhile to have a brief and comprehensive description of:
∑ cell membrane structure and
∑ GI physiology.
5.2.1. Cell Membrane Structure
The cell membranes do form the barriers between various innumerable aqueous compartments present
in the human body. Importantly, even a single layer of membrane is suffi cient to cause an effective sepa-
ration of the ‘intracellular compartments’ from the ‘extracellular compartments’.
Salient Features: They essentially consist of the following:
1. The presence of an epithelial barrier, such as:
(a) gastrointestinal mucosa and
(b) renal tubule,
invariably comprise a ‘layer of cells’ packed and connected tightly to each other in order that ‘drug
molecules’ should critically pass across at least two cell membranes (viz. inner and outer) to sail
through from one side to the other easily and conveniently.
2. Importantly, the vascular endothelium appears to be rather more complex and complicated as well
with regard to its
∑ critical anatomical disposition and
∑ variance in permeability from one tissue to another.
3. Prevailing gaps between the particular endothelial cells are usually packed with a loose matrix of
proteinous matter which more or less acts as ‘fi lters’, thereby helping largely to
∑ retain large molecules and
∑ allow smaller ones to pass through.
4. The actual ‘cut-off molecular size’ appears to be not ‘exact’:
∑ water molecules get transferred rapidly and
∑ drug molecules having molecular size ranging between 80–100 KDa usually get transferred
very sluggishly and gradually.
Essentials of Biopharmaceutics and Pharmacokinetics
46
5. Exceptionally, in CNS and placenta, one may normally come across tight intracellular junctions
existing between
∑ membrane cells and
∑ endothelium
which is encased adequately in an impermeable layer of the ‘periendothelial cells’ (or ‘pericytes’).
Note
In fact, these observed critical features do help in the prevention of potentially harmful and dis-
astrous molecules from being leaked from the circulating blood right into these aforesaid organs
(viz. placenta) and, hence, contribute to much desired major pharmacokinetic consequences for
drug distribution.
6. Interestingly, in liver and spleen, the endothelium is found to be discontinuous, which eventually
permits free passage between the cells. Besides, in liver one may observe critically the occurrence of
‘hepatocytes’ formed duly that serves as the barrier between intra- and extravascular compartments.
The above phenomenon ultimately gives rise to an array of several endothelial cell functionalities.
Routes Adopted by Small Drug Molecules in Crossing Cell Membranes There are in all four
major variants by which the relatively small drug molecules may be able to cross the ensuing cell mem-
branes as shown in Figure 2.9:
∑ effective diffusion directly via the lipid layer,
∑ critical diffusion via the inherent aqueous pores duly formed by specifi c proteins (viz. ‘aquaporins’
23
)
which pass through the lipid,
Figure 2.9 Various routes via which solutes (‘drugs’) can pass across cell membranes.
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23
Aquaporins: They refer to a group of integral membrane proteins that usually function as molecular water
channels to facilitate osmotic movement of water across the plasma membrane. Isolation of Aquaporin-1 from
human erythrocytes/renal tubules [Denker BM et al.: J. Biol. Chem., 263: 15634, 1988].
Biopharmaceutics
47
∑ crucial combination with a specifi c transmembrane-carrier protein which usually binds a drug mol-
ecule on one side of the membrane, and subsequently alters the prevailing conformation and fi nally
release it on the other side of the membrane and
∑ by means of ‘pinocytosis’ i.e., the process by which cells absorb or ingest nutrients and fl uid.
5.2.2. Pathways of Drug Absorption
The oral administration of the drug releases it in the gastrointestinal (GI) fl uids in the form of a solution,
which essentially has the inherent potential of getting absorbed.
24
Obviously, in the absence of any ‘interfering materials’ , which may directly or indirectly affect its
absorption, ultimately ascertains the diffusion from the respective GI fl uid to the corresponding absorb-
able membrane surface. In fact, drug absorption overwhelmingly indicates the penetration of the drug
substance very much across the intestinal membrane. Thus, it subsequently appears in an unaltered form
in the ensuing oozing blood fl ow from the gastrointestinal tract (GIT).
Important Points The above statement of facts suggests two important points vis-à-vis drug absorp-
tion, namely:
∑ As a common practice, it is assumed that the specifi c disappearance of a ‘drug’ from the ensuing
gastrointestinal (GI) fl uids designates drug absorption predominantly; and its immediate appear-
ance in the circulating blood. However, the aforesaid phenomenon does not hold good for such
drug substances that
_ gets duly degraded in GI fl uids or
_ gets adequately metabolized in intestinal cells.
∑ In true sense, the terminology ‘intestinal membrane’ seems to be a misnomer, because the said ‘mem-
brane’ does not represent a unicellular structure but an array of unicellular membranes strategically
positioned parallel to one another. Obviously, for a ‘drug molecule’ to approach the blood stream,
_ it should penetrate the critical mucous layer and
_ it must reach the glycocalyx fully covering the gastrointestinal (GI) lumen, apical cell surface, fl u-
ids within cell, basal membrane, basement membrane, tissue segment of lamina propria, external
capillary membrane, cytoplasm of capillary cell and inner capillary membrane.
In short, it may be added that a particular ‘drug molecule’ to enable its due absorption from the GIT
and to sail across to the systemic blood circulation, it should by all means penetrate effi caciously all
the vital and important segments of the intestinal tract cited above.
There are, in fact, three cardinal factors which predominantly govern the very phenomenon of
absorption, namely:
1. physicochemical properties of ‘drug molecule’,
2. characteristic features and components of ‘GI fl uids’ and
3. nature of the ‘absorbing membrane’.
5.2.3. Gastrointestinal (GI) Physiology
In order to understand the ‘gastrointestinal physiology’, one needs to get familiarized with the major
components of the GI tract—stomach, small intestine and colon (or large intestine). Besides, the small
24
Absorbable Form of Drug: It solely depends upon the physicochemical characteristic feature of the ‘drug’
besides such other environment physical properties, viz. pH, interfering substances and type of absorbing membrane.
Essentials of Biopharmaceutics and Pharmacokinetics
48
intestine essentially comprises such vital segments as duodenum, jejunum and ileum. Interestingly, the
major segments of the GI tract largely differentiate from one another in the following four aspects, such as:
∑ anatomic variance,
∑ morphologic variance,
∑ emanated secretions and
∑ preventing pH.
Figure 2.10 clearly shows the following three most prominent and vital aspects, for instance:
1. human gastrointestinal (GI) tract,
2. anatomy of stomach and
3. anatomical regions of small intestine showing its relatively large surface area.
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Figure 2.10(a) Diagram of a human gastrointestinal (GI) tract.
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Figure 2.10(b) Anatomical regions of the human stomach.
It essentially includes:
For Figure 2.10(a): The GI tract compromises stomach (pH 1–3) having a pylorus (i.e., the
lower portion of the stomach that opens into the duodenum) extending to duodenum (pH 5–7),
jejunum, ileum and fi nally to the ascending colon (pH 7–8).
Explanation