Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
Bioavailability and Bioequivalence
309
Importantly, one may observe that a rapid IV dose would at the same time enable the distribution
through the whole body; whereas, the circulating blood will pass through the liver prominently. In this
way, the drug being distributed in other functional organs is being blocked temporarily from undergoing
the ‘hepatic metabolism’.
Presystemic metabolism can evidently come into play not only confi ned to the ‘liver’ but also in the
‘intestine’ itself or while passing via the intestinal wall. Amazingly, in all these cases, the net overall con-
sequences are duly exhibited by a loss of ‘intact drug’. Till such time a proper logical explanation is not
available for its actual mechanism it may be
∑ explicitly identifi ed as ‘fi rst-pass metabolism’ or
∑ clearly understood as ‘presystemic metabolism’.
Table 5.1 records a comprehensive list of certain important drug substance for which the prevalence of
the ‘presystemic metabolism’ is considered to be quite signifi cant.
Observations: Following are certain important observations:
1. The presystemic metabolism may exhibit a tendency to check and prohibit the oral administration
of a drug substance.
2. Lidocaine (a local anaesthetic) shows a variable and sluggish variable bioavailability on account of
the high fi rst-pass metabolism whereby between 21% and 46% of orally given lidocaine ultimately
reaches the circulating blood.
3. The observed bioavailability of Nortryptyline (a tricyclic anti-depressant) gets reduced upto 40%
(approximately) immediately followed by an oral dose relative to IM administration.
4. Low and variable bioavailability of imipramine ranging between 30% and 75% has been duly
caused due to the fi rst-pass metabolism.
Observed Positive Deviation from Linearity: It has been duly observed that when the fi rst-pass meta-
bolism is extended to saturation level, it is prone to the generation of a critical non-linear dependency for the
Table 5.1 List of certain selected drug substances which may undergo presystemic metabolism when
administered orally
S. No. Drugs S. No. Drugs
1 Paracetamol (acetaminophen) 15 Meperidine
2 Aldosterone 16 Methadone
3 Alprenolol 17 Methylphenidate
4 Aspirin (acetylsalicylic acid) 18 Morphine
5 Chlorpromazine 19 Nitroglycerin
6 Cortisone 20 Nortriptyline
7 Desipramine 21 Papaverine
8 Dopamine 22 Pentazocine
9 Estrogens 23 Propoxyphene
10 Flurazepam 24 Propranolol
11 Hydralazine 25 Salicylamide
12 Imipramine 26 Terbutaline
13 Isoproterenol 27 Testosterone
14 Lidocaine
Essentials of Biopharmaceutics and Pharmacokinetics
310
‘AUC’ as a function of dose. Besides, the exact quantum of the so-called ‘surviving drug’ that eventu-
ally gains entry to the bloodstream gets enhanced by virtue of saturation phenomenon of the respective
enzymes. In this way it produces positive deviation from linearity, as illustrated in Figure 5.9.
0HWDEROLWH
$8&
'UXJ
'RVH
Figure 5.9 Diagrammatic representation of area under the plasma concentration–time curve (AUC)
immediately following the oral absorption of a drug that undergoes saturable fi rst-pass metabolism.
The ‘intact aspirin ester’ reaching the circulating bloodstream gets reduced appreciably on being
released gradually from a sustained-release dosage form (e.g., enteric coated aspirin tablets) in com-
parison to a fast-released aspirin product (e.g., microcrystalline soluble aspirin tablets). Interestingly,
in both these products, the actual bioavailability of total salicylate was more or less identical.
Example
In Figure 5.9 it may be observed that
1. At lower dose levels, practically most of the absorbed drug invariably appears in the plasma
as its respective metabolite.
2. Importantly, at a suffi ciently higher dose level nearing to almost saturate metabolism, the
resulting metabolite critically approaches a constant value, and, therefore, the AUC values
for the drug substance duly increase with the dose.
Explanation
Hollister (1972)
22
observed a similar phenomenon pertaining to the rate of presentation of the drug entity.
22
Hollister LE: Measuring problems in oral prolonged-action medications, Clin. Pharmacol. Ther., 31: 1, 1972.
Bioavailability and Bioequivalence
311
2.7.2. Instability
Generally, a majority of drugs are found to be quite unstable to the following two biological entities, namely:
∑ gastric juice (or acid) and/or
∑ enzymes in GI tract.
Nevertheless, the inevitable ‘hydrolysis of drugs’ usually comes into play particularly in the stomach
fl uids (including gastric juice). Therefore, in such a critical situation when a drug substance undergoes
hydrolysis in the GI tract, it eventually gets involved in the parallel rate processes, as duly expressed by
'UXJ3UHVHQW
LQ
%ORRG
'UXJ
3UHVHQWLQ
*,)OXLGV
N
D
N
K
+\GURO\VHG
'UXJ
3URGXFWV
(
(a)
Thus, the apparent fi rst-order rate constant [k
app
] may be defi ned by
app a h
kkk=+
(b)
where,
k
a
is the rate constant of ‘absorbed drugs’ and
k
h
is the rate constant of ‘hydrolyzed product’.
Therefore, the ultimate ratio of the observed rate constants shall evidently defi ne the ratio of the com-
peting rate phenomena so that we may have the following expression:
h
a
Hydrolyzed product
Drug absorbed
k
k
=
(c)
In Equation (c), the numerator designates the actual quantum of the degradation product (i.e., the
hydrolyzed product), whereas the denominator represents the actual amount of drug being delivered
into the bloodstream.
How does this phenomenon relate to ‘absorption’? We may explain the underlying relationship of the
aforesaid phenomenon to absorption by citing the following typical example:
‘Let us assume that k
h
/k
a
stood at 2, i.e. the rate constant for degradation was ‘twice’ as fast as the
corresponding rate for absorption. In other words, for each and every molecule of drug absorbed, two
molecules will undergo degradation. This obviously indicates that the maximum observed absorption of
the ‘drug’ would turn out to be only 33%.
Important Remarks: The overwhelming problem(s) associated intimately with the ensuing hydrol-
ysis taking place in the ‘gastric fl uids’ are duly focused on two distinct ‘groups of drug substances’, such as:
∑ ‘drugs’ intended for immediate absorption and
∑ ‘drugs’ whose absorption may be delayed critically till they enter the intestines.
23
23
This specifi c category of drugs need to be discussed separately, because it evidently poses the critical problem of
getting the ‘drug’ via the stomach without undergoing degradation at all.
It is worthwhile to state here that the product which specifi cally presented aspirin at a faster
rate (second product) showed eventually a greater AUC for aspirin per se by causing reduction in
the presystemic metabolism.
Essentials of Biopharmaceutics and Pharmacokinetics
312
Hydrolysis of Weak Acidic Drugs (Penicillins) in Gastric Fluids
2
±± ±
&+
&+
&22+
&+
&
1
2
1+ 6
;
3HQLFLOOLQ9
2
+
1
&+
&+
2
+
1
++
6
&22+
$PLQRSHQLFLOODQLF$FLG
>$3$@S.
In penicillin V, the carboxylic moiety of the parent structure, 6-aminopenicillanic acid (6-APA), shows
a pK
a
value in the range 2–3. Thus, the rapid absorption that almost commences in the stomach is very
much desired clinically. One may, however, observe the primary difference in the basic structure of the
penicillins confi ned particularly to the substituents strategically located upon the ‘amide group’ marked X.
Noticeably, this specifi c moiety is solely responsible for the most viable and important difference with
respect to the following aspects:
∑ gastric stability,
∑ enzymatic stability,
∑ drug-protein binding phenomena and
∑ pharmacokinetics.
The following are the various aspects:
1. The presence of β-lactam structure (in penicillins) is found to be highly prone to hydrolysis
thereby causing an overall loss in activity.
2. Another most critical limitation exhibited in the ‘systemic activity of the penicillins’ is per-
haps due to its instability to the enzyme ‘penicillinase’.
24
3. Obvious, instability in gastric juice designates another prominent limitation in the oral
effi cacy of the penicillins.
4. Plasma Half-lives (t
1/2
): The t
1/2
values for the hydrolysis of the penicillins in an aqueous
acidic environment at 35°C are provided duly in Table 5.2 in a summarized form.
Explanation
Observations from Table 5.2 essentially comprise the following:
∑ It is quite evident why ‘methicillin’ (1) is usually dispensed in the form of injectables.
∑ It could be less obvious why ‘penicillin G’ (2) should ever be selected for usual administration via
the oral route. Besides, the bioavailability of penicillin G is found to be variable and not dependable,
which is critically based on the fact that the drug is extremely labile (unstable) to stomach acid (HCl).
∑ ‘Methicillin’(1) possesses an added advantage for being comparatively stable to the enzyme ‘pencil-
linase’. The same also holds good for other penicillin variants, e.g.
_ Oxacillin (5)
_ Cloxacillin.
24
Penicillinase: An enzyme duly produced by the Staphylococcus species of microorganisms.
Bioavailability and Bioequivalence
313
∑ Penicillin G (2) is found to be the ‘least stable’ among all the penicillin variants from (1) through (9).
∑ The rest of the penicillins, viz. 3, 4, 6, 7, 8 and 9 do actually fall between these extremes.
Delaying Absorption until Reaching Intestines Based on the basic ‘pH partition theory’, the unal-
tered form of a drug is invariably absorbed much better in comparison to the charged species. In fact, this
could eventually lead one to believe and expect that the intestinal pH between 6 and 8 may ultimately
allow the critical absorption of:
∑ weakly basic drugs and
∑ non-ionizable drugs.
However, in actual practice, the absorption effi caciousness of the intestines largely predominates over
the theory. Importantly, in a situation where the ‘clinical utility’ of a drug substance does not demand an
immediate onset of action (as seen with chronic dosing), it is defi nitely a viable alternative for promoting
an intentional protection against the so-called ‘gastric dissolution phenomena’.
Example of Erythromycin: It is an acid-unstable drug which is commercially available in various
dosage forms. Erythromycin is found to be most stable between pH 6 and 8, and gets quickly deterio-
rated at pH < 4. Importantly, the ‘protonated version of the erythromycin base’ (see below) exhibits a pK
a
value ~8.9, and, therefore, the drug shall remain in its protonated status all through the GI tract.
3URWRQDWHG9HUVLRQRI(U\WKURP\FLQ%DVH
3URWRQDWHG$PLQH)XQFWLRQ
+2
+1&+
&+
&+
2
2
⊕
Table 5.2 Plasma half-lives (t
1/2
) for the hydrolyzed products of various
penicillins at pH 1.3 and temperature 35°C*
S. No. Penicillin variants Plasma half-lives (t
1/2
, in min)
1 Methicillin 2.3
2 Penicillin G 3.5
3 Phenethicillin 68.0
4
α-Methoxybenzyl penicillin
77.0
5 Oxacillin 160.0
6 Penicillin V 160.0
7
α-Chlorobenzyl penicillin
300.0
8 Amoxicillin 540.0
9 Ampicillin 660.0
* Hou JP and Poole JW: b-Lactam antibiotics: Their physicochemical properties and
biological activities in relation to structure, J. Pharm. Sci., 60: 573, 1971; Sehwartz MA
and Buckwalter FH: Pharmaceutics of penicillin, J. Pharm. Sci., 51: 1119, 1962.
Essentials of Biopharmaceutics and Pharmacokinetics
314
The combination of the aforesaid ‘charged species’ and ‘gastric instability profi le’ perhaps would render
the oral absorption of the drug (erythromycin) not only poor, but also irregular as well. Hence, the best
way to circumvent such an ordeal is to cause an effective intestinal absorption rather than the stomach
absorption. Enhanced GI absorption may be duly accomplished by specifi cally shielding erythromycin
particles from getting exposed to the ‘gastric juices’(or fl uids), which may be carried out by different
well-known recognized modalities:
1. Enteric Coating Preparations: Enteric coating refers to a specialized ‘covering material’ care-
fully applied to granules used in tablets, capsules and pellets (or pills) to protect them and prevent
disintegration or dissolution particularly in the gastric fl uids, thus, enabling the dissolution to be
effective only in the small intestines.
Wagner et al. (1960)
25
reported that the average times taken for the passage of the enteric-coated
tablet right from the stomach to the intestines found to be 3.53 and 2.53 hrs.
2. Using Salts of Erythromycin: The various salts of the tertiary aliphatic amine of erythromycin, such as:
∑ ethylsuccinate,
∑ stearate and
∑ estolate
are also available abundantly besides the enteric coated tablets of ‘erythromycin free base’.
It has been duly reported that the aforesaid salts of erythromycin do not get dissociated so rapidly in
vivo; and therefore, their ultimate degradation retarded signifi cantly.
Important Points Obviously, once present in the intestinal environment, the ‘salt’ undergoes critical
dissociation thereby releasing ‘free erythromycin base’ that eventually gets absorbed at a pH more favour-
able to its desired stability.
Note
As the fi nal disintegration of the ‘dosage form’ takes place in the stomach, one may critically pre-
dict the passage of the ‘drug substance’ more explicitly as a divided powder form.
3. Prodrug of Erythromycin: The lauryl sulphate salt of erythromycin propionate ester designates
the prodrug of erythromycin. Interestingly, the ‘prodrug’ effectively promotes the phenomenon of
absorption in two different manners:
∑ Salts of weak carboxylic acids/erythromycin base do show a tendency to get dissolved in the
‘human gastric fl uid’ predominantly, and lose the antibiotic activity rapidly.
∑ Lauryl sulphuric acid itself being a fairly strong acid prominently resists/prevents the ensuing
displacement by the ‘human-gastric fl uid’.
In this manner, the ‘estolate ester’ not only remains in an ‘undissolved status’, but also retains critically its
desired potency for a longer span of time (Stephens et al. 1959).
26
Complexation Complexation may be defi ned as ‘the physical binding of a chemical, entity with
another substance resulting in a change in properties.’
Scheiner and Altemeier (1962)
27
and Remmers et al. (1965)
28
studied exhaustively the underlying prob-
lem pertaining to the reduced absorption of drug substances due to the complexation with other ‘agents’ in
the respective GI tract, e.g., complexation of the tetracyclines and heavy metal ions (Ca
2+
, Mg
2+
, Fe
2+
, Al
3+
).
25
Wagner et al.: Enteric coatings IV, J. Pharm. Sci., 49: 128, 1960.
26
Stephens VC et al.: Esters of Erthromycin IV, J. Pharm. Sci., 48: 620, 1959.
27
Scheiner J and Altemeier WA: Surgery, 114: 9, 1962.
28
Remmers RG et al.: J. Pharm. Sci., 54: 49, 1965.
Bioavailability and Bioequivalence
315
Salient Features: These essentially comprise the following:
1. The co-administration of aluminium hydroxide gels [Al(OH)
3
], milk and milk products along with
the tetracyclines apparently reduce nausea and vomiting.
This could be explained by the fact that complexation of ‘tetracyclines’ with Al
3+
, Ca
2+
etc., invariably
occurs that might glaringly minimize such symptoms (nausea/vomiting), because the generated ‘com-
plex’ turns out to be quite inactive and hence unable to penetrate the surrounding biological membrane.
Explanation
2. As the ‘tetracyclines’ quite often imbalance the normal GI fl ora, the complexation may cause a
decreased GI distress, whereas, the source results could be accomplished by replacing tetracyclines
with other antibiotics.
2.8. Factors that Increase Bioavailability
It has been established beyond any reasonable doubt that specifi cally enhancing the lipophilicity of a
drug substance proves to be one of the most important and viable approaches to improve upon the drug’s
so-called ‘passive transport’ (Section 2(6.5)) . Importantly, by virtue of the increased bioavailability it
may now be possible and feasible to minimize the actual intended dose of drug. In other words, the
overall therapeutic treatment eventually is rendered not only ‘more economical’, but also causes apparent
minimization of the ‘undesirable side effects’ intimately associated with the relatively high dose of drug.
An obvious poorly bioavailable drug product (or dosage form) should exhibit the following four
characteristic features:
∑ Extremely low (poor) hydrophilicity (or aqueous solubility), and/or slow dissolution rate in the
biological fl uids.
∑ Signifi cantly poor stability of the dissolved drug at the physiologic pH (in vivo).
∑ Insuffi cient partition coeffi cient of drug product thereby giving rise to sluggish permeation via the
biomembranes.
∑ An overall extensive presystemic metabolism.
2.8.1. Overcoming Acute Bioavailability Issues
In order to overcome various acute bioavailability issues, one may make use of any one of the following
three modus operandi:
1. Pharmacokinetic Means: It essentially engages critical modifi cation in the chemical structure of
the drug molecule to afford a change in the pharmacokinetic profi le of drug product.
Following are some of the typical examples:
Acetonidation (or Esterifi cation) of Corticosteroids: The prodrug approach to ‘fl uo-
cinolone’ remarkably enhances the extremely low skin permeability of this steroidal drug,
containing hydroxyl moieties is mainly attributed to its specifi c interaction with
∑ skin (epidermis) and
∑ binding sites in keratin.
29
Example
29
Keratin: It refers to any of a family of scleroproteins that are the main constituents of epidermis, hair, nails and
horny tissues.
Essentials of Biopharmaceutics and Pharmacokinetics
316
Thus, acetonidation (or esterifi cation) of corticosteroids (fl uocinolone) enhances the permeability
to skin perceptively. Interestingly, the fl uocinolone acetonide (a ‘prodrug’ belonging to the corti-
costeriod class) is abundantly useful in these two well-known skin manifestations, such as:
∑ infl ammatory conditions and
∑ pruritic conditions.
The ‘prodrug’ gets duly activated in vivo by the enzyme esterase
Prodrug of Fluclorolone (or Flucocinolone)
)OXFORURORQHRU
)OXFRFLQRORQH
$FHWRPLGH
)OXFORURORQH
RU)OXFRFLQRORQH
5 +
5 &
2
&+
&O
2
52
2
2
&+
&+
&+
&+
2
+
)
+
&O
Acyclovir (an antiviral drug) inherently possesses poor bioavailability on account of its three
prominent properties, for instance,
∑ extremely low solubility,
∑ poor GI absorption rate and
∑ biotransformation to an ‘inactive metabolite’.
A precurson-type of prodrug, 6-deoxyacyclovir, gets duly oxidized by the help of the enzyme
‘xanthine oxidase’ to reproduce acyclovir.
30
Amazingly, the prodrug, i.e., 6-deoxyacyclovir, is
remarkably found to be showing:
∑ 18-fold greater water solubility and
∑ 5–6-fold higher bioavailability after oral administration.
Example
30
Acyclovir: It is active against herpes simplex viruses (HSV) 1 and 2, varicella zoster, Epstein-Barr viruses and
cytomegalovirus.
2. Pharmaceutic Approach: The pharmaceutic approach involves particularly the modifi cation(s)
of the ‘drug entity’ with respect to the following aspects:
∑ formulation fundamentals,
∑ manufacturing process and
∑ physicochemical properties of the drug substance, without altering its basic chemical structure.
Bioavailability and Bioequivalence
317
[A Precursor-Type Prodrug]
;DQWKLQH
2[LGDVH
(Q]\PH
'HR[\DF\FORYLU
$F\FORYLU
+
1
2
1
1
1
1
1
1
1
+1
&+
2&+
&+
2+
+
1
&+
2&+
&+
2+
The following well-known ‘general anaesthetics’ are administrated via the IV route:
Barbiturates—Thiopental sodium,
Non-Barbiturates—Propofol, etomidate, ketamine.
Example
2.8.2. Physicochemical Characteristics of a Drug
The host of diversifi ed and judicious attempts dealing with such focused activities, such as:
∑ formulation optimization,
∑ manufacturing protocols and
∑ physicochemical characteristic of a drug
are invariably carried out so as to accomplish an increase in the ‘dissolution rate’, since it categorically
represents the most critical and major ‘rate-limiting step’ in the actual absorption of an array of drug sub-
stances. Based on the literature survey, it has been amply demonstrated that the ensuing ‘dissolution rate
of a drug’ may be increased appreciably through many well-known means and ways. Following are some
of the predominant time-tested and tried procedures, a majority of which are usually aimed at enhancing
the prevailing ‘surface area of the drug substances’, and will be discussed briefl y in the following sections.
Micronization Micronization actually refers to the reduction of particles to
micrometre diameter sizes
specifi cally.
In actual practice, micronization essentially involves the critical reduction of the solid drug particulate
matter between 1–10 micrometre (μm) [∫ 0.000,001 m]. This may be duly obtained by
∑ ‘spray-drying process’
31
or
∑ ‘fl uid-energy mill’
32
(or air-attrition techniques).
31
Spray-Dryer: It refers to a machine that removes moisture from ‘atomized particles’, almost instantaneously,
using a controlled ‘solution feed’ through a high rpm wheel (atomizer) and an upward fl ow of heated air. Particles
are dried as they fall through the heated air (fl uidized bed) in an enclosed SS chamber and are duly collected in a
container at the bottom of the chamber. The moisture-laiden vapour is vented up and escapes out of the chamber.
32
Fluid-Energy Mill: It is a device used to reduce particle size by rotating particles at high speeds in a bed of air
against the sides of a chamber and against other particles. The particles get duly reduced in size by attrition and
mostly obtained in spherical shape.
3. Biologic Method: The biologic method essentially deals with the ‘route of drug administration’
which could be altered suitably to retain the maximum desired bioavailability of the drug released
from the respective dosage form, e.g., from ‘oral route’ to the corresponding ‘parenteral route’.
Essentials of Biopharmaceutics and Pharmacokinetics
318
The ‘micronization’ of a drug substance shall critically enhance the solubility profi le in the small intestine,
which happens to be a better absorption site but at the same time there would be a defi nite ‘increased
rate of drug degradation’ in the stomach perhaps due to the induced and increased ‘surface area’.
Surfactants (or Surface-Active Agents) The ‘surfactant’ invariably refers to a substance that
minimizes
∑ surface tension and
∑ interfacial tension,
particularly in small concentrations. The most common examples of the ‘surfactants’ are emulsifi ers,
defl oculants, suspending oils, dispersants, soaps and detergents.
The surfactants specifi cally increase the dissolution rate primarily due to the dual functional phe-
nomena, namely:
∑ augmentation of ‘wetting’ and
∑ penetration of ‘dissolution fl uid’,
right inside the solid-drug particulate matter.
In usual practice, the surfactants are employed at a concentration level much below their actual criti-
cal micelle concentration (CMC)
33
values, because above CMC, the drug substance thus entrapped into
the micelle structure does not undergo partition in the dissolution medium at all.
Non-ionic Surfactants—These designate such surface-active agent (or surfactants) that fails to get ion-
ized in solution. In fact, they do exhibit fewer chemical incompatibilities in comparison to other surfactants.
Following are certain typical examples of drug substances:
1. Aspirin—for getting relief from headache rapidly.
2. Sulpha drugs—for rapid bioavailability.
3. Griseofulvin—for much faster, safer and rapid absorption in vivo.
4. Steroidal drugs—being bulky, water immiscible nature need to be obtained in micronized
for quick absorption in vivo.
Examples
Tween 80, Polysorbate 80, Tween 20 etc.
Examples
Note
Spironolactone (an aldosterone diuretic) has its bioavailability increased signifi cantly by making
use of the surfactants in the drug formulation.
33
Critical Micelle Concentration (CMC): CMC refers to the concentration of an amphiphile (i.e., a molecule
having affi nity for both aqueous and lipid media) above which micelles begin to generate.