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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
Biopharmaceutics
119
∑ secretion,
∑ digestion and
∑ absorption.
However, the important functional components of the GIT (entire length: 450 cm) are namely: stom-
ach, small intestine (comprising duodenum, jejunum and ileum) and the large intestine (also known a
colon), which distinctly and grossly differ from one another in terms of their individuals pH, anatomy,
functions and secretions (see Figure 2.36).
Note
The complete length of the GI mucosa right from stomach to the large intestine is meticulously lined
by a thin layer of ‘mucopolysaccharides’ (viz. mucus/mucin) that invariably serves as an impermeable
barrier to the specialized particulate matters, for instance food particles, cells or microorganisms.
Stomach: It is more or less a ‘sac-like structure’ with a smooth mucosa and, of course, a small surface
area. The acidic secretion in stomach due to HCl maintains a pH between 1 and 3, which predominately
favours the critical absorption of the ‘acidic drugs’, after getting duly solubilized gastric juice, because
they do remain largely in an unionized state large degree in an acidic pH.
Besides, the acidic gastric juice (pH 1–3) helps in the proper dissolution of a host of basic drugs by
virtue of their respective salt formation. Thus, their subsequent ionization renders them from being
absorbed to a much lesser degree from the ensuing stomach.
Small Intestine: It actually represents the major site for the most preferred absorption of array of
‘active drugs’ based on the availability of a huge surface area. The folds of Kerckring, as could be seen in the
intestinal mucosa, renders the surface area to almost three times. Further more, ‘villi’, i.e., the fi nger-like
projections, almost enhances the exposed surface area to almost 30 folds. The resulting microvilli increases
each absorptive cell lines up to 600 folds. Thus, the overall dimensions of the small intestine are as following:
Length: ~285 cm
Surface Area: ~200 sq. m.
The observed blood fl ow in the small intestine ranges between 8 and 10 folds than that of the stom-
ach. Interestingly, the prevailing pH range between 5 and 7.5 proves to be the most desirables and favour-
able for a good number of ‘active drugs’ belonging to the therapeutic armamentarium, which remain
unionized virtually.
In short, based on the above enormous advantageous plus points, the ‘intestine’ is proved to be the
best available recognized acceptable site for the critical absorption of a host of drugs.
Large Intestine: Both the length (110 cm) and the mucosal surface area (0.15 sq. m) are smaller
when compared to villi/ microviili/small intestine and, therefore, the ultimate absorption of drugs from
‘colon’ appears to be almost insignifi cant.
The large intestine plays two major roles, namely:
∑ enormous absorption of water and electrotypes and
∑ excessive residence time (6–8 hrs)—the ‘colonic transit’ may prove to be quite vital and important
in the critical absorption of certain sparingly soluble drugs, and also some sustained release drug
products (or dosage forms).
The various patient-related factors have been discussed elsewhere in this chapter.
Essentials of Biopharmaceutics and Pharmacokinetics
120
Suggested Readings
Cadawallader DE. Biopharmaceutics and Drug Interactions, 3rd edn. New York: Raven Press, New York, 1983.
Gennaro AR. Remington: The Science and Practice of Pharmacy, 20th edn., Vols. 1. and 2. New York: Lippincott Williams &
Wilkins, 2004.
Gibaldi M, Perrier D. Pharmacokinetics, 2nd edn. New York: Marcel Dekker Inc., 1982.
Notari RE. Biopharmaceutics and Clinical Pharmacokinetics, 4th edn. New York: Marcel Dekker Inc., 1987.
Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edn. Philadelphia, PA: Lea &
Febiger, 1995.
Shargel L, Yu ABC. Applied Biopharmaceuties and Pharmacokinetics, 4th edn. New York: McGraw Hill Medical Pub-
lishing, 1999.
Swarbick J (Ed.). Encyclopedia of Pharmaceutical Technology, 3rd edn., Vol. 1. New York: Informa Healthcare USA
Inc, 2007.
SECTION 3
Pharmacokinetics
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3
Pharmacokinetics
CHAPTER OUTLINE
1. Introduction
2. Clinical Signifi cance of Plasma Protein Drug
Concentration Measurement
3. Pharmacokinetic Models
4. Pharmacokinetics of Drug Absorption
5. Volume of Distribution and Distribution Coeffi cient
6. Organ-Specifi c Clearance
7. Non-Linear Pharmacokinetics
8. Pharmacokinetic Profi les of Some Specifi c Examples
from Various Classes of Drugs
1. Introduction
Pharmacokinetics is defi ned as ‘the study of the quantitative relationships of the rates of drug absorption,
distribution and elimination process: data used to establish dosage amount and frequency for the desired
therapeutic response’.
The term ‘pharmacokinetics’ was fi rst introduced by Professor Dost (1953)
1
in his text “Der
Blutspiequelkinetic der Konzentration-sablauffe in der Kreislauffl ussiqkeit.”
Though the concept of pharmacokinetics and compartment analysis is certainly not a new one, yet
the intrinsic level of interest and sophistication in this particular fi eld has increased almost rapidly in the
recent past. In 1920, the Swedish scientists fi rst initiated the preliminary investigative studies related to
the kinetics of drug elimination, and drug plasma concentration levels after administration of multiple
doses. However, within a span of two decades the ‘compartmental model’ was duly introduced followed
by a comprehensive report pertaining to the kinetics of the distribution profi le of drug substances in vivo.
Nelson (1961)
2
fi rst and foremost presented a ‘review on pharmacokinetics’ with regard to drug
absorption, distribution, metabolism and excretion (ADME). Notari (1980)
3
established a logical cor-
relation between ADME of drug substances and their inherent pharmacologic, therapeutic or toxic
1
Dost FH: Drug Intell. Clin. Pharm., 11: 747, 1953.
2
Nelson E: J. Pharm. Sci., 50: 181, 1961.
3
Notari RE: Biopharmaceutics and Clinical Pharmacokinetics, 3rd edn., New York: Marcel Dekker Inc., 1980, pp. 3, 46–47.
Essentials of Biopharmaceutics and Pharmacokinetics
124
response in animals and humans. Importantly, the development of mathematical models is an absolute
requirement to the interpretation of the typical prevailing kinetic phenomena.
The various important aspects of pharmacokinetics shall be discussed in an elaborated manner using
appropriate examples wherever necessary in the following sections.
2. Clinical Significance of Plasma Protein Drug Concentration Measurement
It has been duly demonstrated that most drug molecules in vivo (i.e., in a human body after administra-
tion of a drug) do invariably show a tendency to undergo critical interaction with several tissue constitu-
ents of which the two major recognized categories are:
∑ plasma protein (available in circulating blood) and
∑ cardiovascular tissues.
Importantly, an array of typical ‘macromolecules’, e.g., deoxyribonucleic acid (DNA–a nucleic acid),
plasma protein (obtained from human blood) and adipose tissue (fat depots in a human body) are ade-
quately formed by the interacting molecules, i.e., the drug-protein binding. Therefore, one may logically
explain the ‘protein-binding of drugs’ as caused by the unique process of complex formation of drugs
and proteins. In reality, the different blood proteins to which the ‘drugs’ usually bind are:
∑ human serum albumin,
∑ α
1
-acid glycoprotein and
∑ lipoproteins.
It is, however, important to state here that the respective ‘protein-bound drug’ entity due to its relatively
large size fail to pass across the cell membranes. On the contrary, the corresponding ‘unbound drug’
entity can pass through various cell membranes easily and conveniently.
Therefore, in usual practice, based on the ease of detection, one may determine the drug concentra-
tion in plasma rather than the assay of free-drug concentration. Perhaps for the same good logical expla-
nation, the so-called ‘recommended therapeutic concentrations’ are frequently expressed in terms of the
‘total drug concentration in plasma’.
Note
Methods employed for measuring free-drug concentration are found to be time consuming, tedi-
ous and expensive, and show lack of accuracy and precision in results and, therefore, are totally
replaced by the assay for ‘total drug concentration in plasma’.
2.1. Significance of Drug–Protein Binding Complex
The vital signifi cance of drug–protein binding complex is as enumerated below:
1. Inert Pharmacokinetically—These complexes are found to be quite inert pharmacokinetically.
2. Inert Pharmadynamically—These complexes strongly suggest that why a ‘protein-bound drug’
entity largely behaves as:
∑ ineffective towards mobilization in vivo,
∑ non-excretable via the biological system,
∑ fails to exert any pharmacological activity in vivo,
Pharmacokinetics
125
∑ remains confi ned to a specifi c tissue for which it shows an enhanced affi nity level and
∑ retards signifi cantly the ‘free membrane transport’ due to its huge bulk size, thereby increasing
the biological half-cycle (t
1/2
) appreciably.
The critical and specifi c binding of drugs to the different tissue constituents vis-à-vis its concerted
response to either meaningful disposition or anticipated clinical effect is as depicted in Figure 3.1.
Generally, the drug-protein binding process designates a reversible process. Nevertheless, a few typical
drug substances may bind to proteins in an irreversible manner, e.g., the specifi cally reactive intermediate
metabolites of paracetamol
4
at higher dosage regimens that bind with liver proteins irreversibly and thus
give rise to an ultimate status of hepatotoxicity.
How Does ‘Binding of Drugs’ Commence in vivo?: On the basis of the copious volumes of extensive
and intensive research outputs across the globe, one may rightly arrive at the following two important
reasons concerned with the ‘binding of drugs’:
1. Blood constituents, e.g., plasma or blood cells and
2. Extracellular tissue proteins, e.g., adipose tissues, bone marrow, cardiovascular tissues.
Table 3.1 records explicitly the ‘blood proteins’ that get bound to different ‘drug substances’.
Importantly, the ‘binding of drugs’ systematically takes place in a human body at various ports, namely:
∑ serum albumin,
∑ α
1
-acid glycoprotein (also known as α
1
-AGP or AAG),
∑ lipoproteins,
∑ globulins and
∑ erythrocytes [or red blood cells (RBCs)],
which shall now be discussed individually in the following sections.
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distribution-metabolism-excretion (via kidney)-therapeutic effect.
4
Paracetamol: It is also known as ‘acetaminophen’ in USA.
Essentials of Biopharmaceutics and Pharmacokinetics
126
2.1.1. Serum Albumin
Obviously, serum albumin renders the most vital and prominent contribution to drug binding in the
plasma that almost constitutes 50% of the total plasma proteins having a concentration ranging between
3.5% and 5%. In fact, the human serum albumin (HSA) is largely synthesized by liver, and has a molecu-
lar weight varying between 65K and 69K Da. The following are the important characteristics of HSA:
∑ HSA is usually present in plasma and extracellular fl uid of different tissues.
∑ Nearly 120 g albumin is present in plasma for a man weighing 70 kg.
∑ Approximately 60% of total albumin in a human body is invariably found outside the plasma.
∑ Lower concentrations of serum albumin are usually found in pregnancy and some other disease
conditions.
∑ HSA critically maintains the osmotic pressure of the blood.
∑ HSA takes care for the crucial in vivo transportation of
_ endogenous substances
5
and
_ exogenous materials.
∑ Albumin gets bound to a good number of weak acidic drugs and neutral drugs.
Different Sites on HSA for Drug-Binding: In fact, there exist four different critical sites strategically
located on HSA which have been duly identifi ed and recognized for drug binding, as illustrated in Figure 3.2.
Table 3.1 Different blood proteins to which drugs usually bind
S. No. Blood protein
Molecular weight
(Da)
Concentration [%] Drugs binding to protein
1 Human serum albumin 65,000–69,000 3.5–5 Broad spectrum of most drug
substances
2
α
1
-Acid glycoprotein
(orosomucoid)
44,000 0.04–0.1 Imipramine, lidocaine, quinidine
(i.e., basic drug substances)
3 Lipoproteins (i.e.,
macro- molecular
complexes of lipids
and proteins
2,000,000–
3,400,000
Occurs in a
variable range
Chlorpromazine (i.e., basic
lipophilic drug)
4
α
1
-Globulin
59,000 0.003–0.007 Cyanocobalamine (vitamin B
12
),
thyroxine and corticosterone
(a corticosteroid)
5
α
2
-Globulin
1,34,000 0.015–0.06 Fat soluble vitamins, viz.
vitamins A, D, E and K; and
Cu
2+
(cupric ions)
6 Haemoglobin 64,500 11–16 Phenobarbital, phenytoin and
phenothiazines
5
Endogenous Substances: Albumin undergoes complexation with bilirubin, free-fatty acids (FFAs), tryptophan, and
a number of hormones (viz. aldosterone, cortisone, thyroxine etc.) to serve as a ‘transport protein’ for the endogenous
substances.
Pharmacokinetics
127
Site 2: Diazepam Binding Site—It refers to such drug substances that particularly bind to this region
and essentially comprise benzodiazepines, cloxacillin, ibuprofen, ketoprofen, medium chain fatty acids
(MCFAs), probenecid and tryptophan.
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Figure 3.2 Diagrammatic representation of four major drug binding sites on human serum albumin (HSA).
NSAIDs, viz. indomethacin, naproxen and phenylbutazone; sulphonamides, viz. sulphamethizole,
sulphadimethoxine; phenytoin; bilirubin; sodium valproate.
Examples
Note
It is worthwhile to state here that ‘Site 1’ and ‘Site 2’ are solely responsible for enabling
the maximum quantum of drug-binding sites.
Site 3: Digitoxin Binding Site—Rarely a few drugs get bound to this site.
Site 4: Tamoxifen Binding Site—It also serves as a remote site for drug binding.
Salient Features for Binding Sites: There are quite a few salient features with particular reference
to the available binding sites, namely:
1. A specifi c ‘drug’ may easily get bound to more than one site. In such a situation, one may call the
main-binding site as the ‘primary site’ while the less prominent binding site as the ‘secondary site’.
Explanation
Following are the brief explanations with regard to the aforesaid four distinct drug binding sites:
Site 1: Warfarin (or Azapropazone) Binding Site—It mostly designates the specifi c region at which a
large number of drug substances usually get bound appropriately:
Essentials of Biopharmaceutics and Pharmacokinetics
128
2. Certain groups of drugs that usually bind to the same site are found to compete with each other
for binding progressively.
Dicoumarol (a natural anti-coagulant) has the following two distinct sites:
∑ Site 1—refers to the ‘primary site’ and
∑ Site 2—designates the ‘secondary site’.
Example
Sulphonamides for Site 1.
Example
3. Some drugs which critically get bound to one site are found not to inhibit competitively the bind-
ing of drugs to other sites at all.
Cloxacillin and ketoprofen that usually bind to Site 2 exclusively.
Examples
2.1.2. a
1
-Acid Glycoprotein (or a
1
-AGP or AAG)
It is also termed as the orosomucoid which represents a low molecular weight (~ 40,000 Da) protein
and is a ‘globulin’. Usually, the average plasma concentration of α
1
-acid glycoprotein per 100 mL ranges
between 40 and 100 mg.
Important Features: α
1
-AGP (or AAG) has two important features, namely:
∑ Its concentration in the plasma gets elevated in certain typical disease conditions, viz.
_ infl ammation,
_ excessive physical/mental stress and
_ several malignant disease states.
Besides, one may critically observe a marked decrease in plasma concentration of AAG in such dis-
ease conditions as:
_ nephritic syndrome and
_ hepatic diseases.
∑ It primarily gets bound to a good number of basic drug entities, e.g., imipramine, lidocaine, pro-
pranolol and quinidine.
In a broader perspective, one may obviously visualize the most vital aspects pertaining to protein
binding duly found to be quite variable among the patients having altogether variant therapeutic status.
Amazingly, several diseases may change perceptively the drug-protein bindings by reducing signifi cantly
the quantum of proteins available readily for binding phenomena, as shown in Table 3.2.
Extent of Drug-Protein Binding: The actual extent of drug-protein binding is expressed invariably
as the ratio of bound drug to total drug concentration.
The observed ratio usually ranges between 0 and 1. The drugs having a ratio of more than 0.9 are
regarded to be falling under the category of ‘highly protein-bound drugs.’
Importantly, the ability of drug–protein binding shall solely depend upon the molar concentrations
of drug and protein specifi cally.