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PHAR 9926
Basic Pharmaceutics and Calculations
Drug Interaction-2
Plasma Protein – Binding Displacement
Applied Biopharmaceutics & Pharmacokinetics, 7e Chapter 10
Applied Clinical Pharmacokinetics, Chapter 2, Larry Bauer
Clinical Pharmacokinetics and Pharmacodynamics, 4th Ed., Malcolm Rowland &Thomas N. Tozer
Protein Binding
 Many drugs interact with plasma or tissue proteins or with other
macromolecules, such as melanin and DNA, to form a drug–
macromolecule complex.
 The formation of a drug–protein complex is often named drug–
protein binding.
 Drug–protein binding may be a reversible or an irreversible
process.
 Irreversible drug–protein binding is usually a result of chemical
activation of the drug, which then attaches strongly to the protein
or macromolecule by covalent chemical bonding. Irreversible drug
binding accounts for certain types of drug toxicity that may occur
over a long time period, as in the case of chemical carcinogenesis,
or within a relatively short time period, as in the case of drugs that
form reactive chemical intermediates.
Eg.: the hepatotoxicity of high doses of acetaminophen is
due to the formation of reactive metabolite intermediate that
interact with liver proteins.
Protein Binding
 Most drugs bind or complex with proteins by a reversible
process.
 Reversible drug–protein binding implies that the drug
binds the protein with weaker chemical bonds, such as
hydrogen bonds or van der Waals forces.
 The amino acids that compose the protein chain have
hydroxyl, carboxyl, or other sites available for reversible
drug interactions.
 Reversible drug–protein binding is of major interest in PKs.
 The protein-bound drug is a large complex that cannot easily
transverse the capillary wall and therefore has a restricted
distribution.
 Moreover, the protein-bound drug is usually pharmacologically
inactive.
Protein Binding
 The free or unbound drug crosses cell membranes and is
therapeutically active.
 Studies that critically evaluate drug–protein binding are usually
performed in vitro using a purified protein such as albumin.
 Methods including equilibrium dialysis and ultrafiltration, make
use of a semipermeable membrane that separates the protein and
protein-bound drug from the free or unbound drug.
Protein Binding
 Drugs may bind to various macromolecular components in the
blood, including albumin, α1-acid glycoprotein, lipoproteins,
immunoglobulins (IgG), and erythrocytes (RBC).
Major Proteins to Which Drugs Bind in Plasma
Protein
Molecular Weight (Da)
Albumin
Normal Range of Concentrations
(g/L)
(mol/L)
65,000
35–50
5–7.5 × 10
α1-Acid glycoprotein
44,000
0.4–1.0
0.9–2.2 × 10
Lipoproteins
200,000–3,400,000
Variable
–4
–5
 Albumin is a protein with a molecular weight of 65,000 to 69,000
Da that is synthesized in the liver and is the major component of
plasma proteins responsible for reversible drug binding.
 In the body, albumin is distributed in the plasma and in the
extracellular fluids of skin, muscle, and various other tissues.
Interstitial fluid albumin concentration is about 60% of that in the
plasma.
Protein Binding
 The elimination half-life of albumin is 17 to 18 days. Normally,
albumin concentration is maintained at a relatively constant
level of 3.5% to 5.5% (weight per volume) or 4.5 mg/dL.
 Albumin is responsible for maintaining the osmotic pressure of
the blood and for the transport of endogenous and exogenous
substances in the plasma.
 Albumin complexes with endogenous substances such as free
fatty acids (FFAs), bilirubin, various hormones (eg, cortisone,
aldosterone, thyroxine, tryptophan), and other compounds.
 Many weak acidic (anionic) drugs bind to albumin by
electrostatic and hydrophobic bonds.
 Weak acidic drugs such as salicylates, phenylbutazone, and
penicillins are highly bound to albumin. However, the strength of
the drug binding is different for each drug.
Protein Binding
 Alpha-1-acid glycoprotein (AAG) is a globulin with a
molecular weight of about 44,000 Da.
 The plasma concentration of AAG is low (0.4%–1%) and
it binds primarily basic (cationic) drugs such
as saquinavir, propranolol, imipramine, and lidocaine.
 Globulins (α-, β-, γ-globulins) may be responsible for the
plasma transport of certain endogenous substances
such as corticosteroids.
 These globulins have a low capacity but high affinity for
the binding of these endogenous substances.
Effect of protein binding on the apparent vd
 The extent of drug protein binding in the plasma or tissue
affects Vd.
 Drugs that are highly bound to plasma proteins have a low fraction
of free drug (fu = unbound or free drug fraction) in the plasma
water.
 The plasma protein-bound drug does not diffuse easily and is
therefore less extensively distributed to tissues.
 Drugs with low plasma protein binding have larger fu, generally
diffuse more easily into tissues, and have a greater Vd.
 Although the apparent Vd is influenced by lipid solubility in
addition to protein binding, there are some exceptions to this rule.
When several drugs are selected from a single family with similar
physical and lipid partition characteristics, the apparent Vd may be
explained by the relative degree of drug binding to tissue and
plasma proteins.
Effect of protein binding on the apparent vd
Plot of Vd of four cephalosporin antibiotics in humans and
mice showing the relationship between the fraction of
unbound drug (fu) and the volume of distribution. (Data from
Sawada et al, 1984.)
Effect of protein binding on the apparent vd
 Drugs such as furosemide, sulfisoxazole, tolbutamide,
and warfarin are bound greater than 90% to plasma
proteins and have a Vd value ranging from 7.7 to 11.2 L
per 70-kg body weight.
 Basic drugs such as imipramine, nortriptyline, and
propranolol are extensively bound to both tissue and
plasma proteins and have very large Vd values.
Mouse Model
Imipramine Level (ng/mL)
Serum
Brian
Normal
319.9
7307.7
Transgenic
859
3862.6
Transgenic animals that have 8.6 times the normal AAG levels
Selected physiological parameters in mouse (0.02kg), rat(0.25kg), rabbit (2.5kg), monkey
(5.0kg), dog (10kg) and man (70kg) – useful for pharmacokinetic interpretation.
Volumes(ml)
Mouse
Rat
Rabbit
Monkey
Dog
Human
Total body water
14.5
167
1790
3465
6036
42000
Intracellular fluid

92.8
1165
2425
3276
23800
Extracellular fluid

74.2
625
1040
2760
18200
Plasma volume
1.0
7.8
110
224
515
3000
http://rmi-pharmacokinetics.com/Physiological_parameters
Selected physiological parameters in mouse (0.02kg), rat(0.25kg), rabbit (2.5kg), monkey
(5.0kg), dog (10kg) and man (70kg) – useful for pharmacokinetic interpretation.
Organ weights (g)
Mouse
Rat
Rabbit Monkey
Brain
0.36
1.8
14
90
80
1400
Liver
1.75
10.0
77
150
320
1800
Kidneys
0.32
2.0
13
25
50
310
Heart
0.08
1.0
5
18.5
80
330
Spleen
0.1
0.75
1
8
25
180
Adrenals
0.004
0.05
0.5
1.2
1
14
Lung
0.12
1.5
18
33
100
1000
http://rmi-pharmacokinetics.com/Physiological_parameters
Dog Human
Effect of protein binding on the apparent vd
 Displacement of drugs from plasma proteins can affect its PKs by:
(1) directly increasing the free (unbound) drug concentration as a
result of reduced binding in the blood;
(2) increasing the free drug concentration that reaches the
receptor sites directly, causing a more intense
pharmacodynamic (or toxic) response;
(3) increasing the free drug concentration, causing a transient
increase in Vd and decreasing partly some of the increase in
free plasma drug concentration;
(4) increasing the free drug concentration, resulting in more
drug diffusion into tissues of eliminating organs(the liver and
kidney), resulting in a transient increase in drug elimination.
 The ultimate drug concentration reaching the target depends on
one or more of these four factors dominating in the clinical
situation. The effect of drug–protein binding must be evaluated
carefully before dosing changes are made.
Drug with a Large Vd and a Long t1/2
 The macrolide antibiotic dirithromycin is extensively
distributed in tissues, resulting in a large steady-state Vd of
about 800 L (504–1041 L).
 The elimination t1/2 in humans is about 44 hours (16–65 hr).
 The drug has a relatively large total body clearance of 226 to
1040 mL/min (13.6–62.4 L/hr) and is given once daily.
 In this case, clearance and Vd are large, whereas k is
relatively small and t1/2 is long because of the large Vd.
 Intuitively, the drug will take a long time to be removed when
the drug is distributed extensively over a large volume;
despite a relatively large clearance, t1/2 accurately describes
drug elimination alone.
Drug with a Samll Vd and a Long t1/2
 Tenoxicam is a NSAIDs with fu of 1.0%. The drug has low
lipophilicity, is highly ionized (~ 99%), and is distributed in blood and
penetrates cell membranes very slowly. The synovial fluid peak drug
level is only 1/3 that of the Cp and occurs 20 hr (10–34 hr) later than
the peak plasma drug level.
 It has an apparent, Vd, of 9.6 L (7.5–11.5 L).
 Tenoxicam has a low total Cl of 0.106 L/h and an t1/2 of 67 hr, which
related to the extensive drug binding to plasma proteins.
 Based on Cl=Vd*k, then Cl will be low with low Vd and not too large k.
 This relationship is consistent with a small Cl and a small Vd
observed for tenoxicam. Equation
, however, predicts that
a small Vd would result in a short t1/2.
 In this case, the actual t1/2 is long (67 hr) because the plasma
tenoxicam Cl is so low.
 The long t1/2 of tenoxicam is better explained by its low Cl due to its
binding to plasma proteins, results in slow clearance of drug.
DETERMINANTS OF PROTEIN BINDING
Drug–protein binding is influenced by a number of important factors,
including the following:
 The drug
-Physicochemical properties of the drug
-Total concentration of the drug in the body
 The protein
-Quantity of protein available for drug–protein binding
-Quality or physicochemical nature of the protein synthesized
 The affinity between drug and protein
-The magnitude of the association constant
 Drug interactions
-Competition for a protein-binding site
-Alteration of the protein by a substance that modifies the affinity
of the drug for the protein; for example, aspirin acetylates lysine
residues of albumin
 The pathophysiologic condition of the patient
-For example, drug–protein binding may be reduced in uremic
patients and in patients with hepatic disease
Drug Interactions: Competition for Binding Sites
 When a highly protein-bound drug is displaced from binding by a
second drug or agent, a sharp increase in the free drug concentration in
the plasma may occur, leading to toxicity.
• eg., an increase in free warfarin level was responsible for an
increase in bleeding when warfarin was coadministered with
phenylbutazone, which competes for the same protein-binding site.
 Since protein binding and metabolism both occur in vivo and can both
influence the rate of metabolism in a patient, it is not always clear
whether to attribute the cause of a change in metabolism based on
kinetic observations alone.
 Change in CYP enzymes may occur in genetic polymorphism and at the
same time change in protein may occur due to a number of causes.
 After reviewing many examples of drug–protein binding, it has been
concluded that appropriate analysis requires careful consideration of
both pharmacokinetic and pharmacodynamic processes, as they both
contribute to the safety and efficacy of drugs.
 Ideally, the free drug concentrations at the receptor site should be used
for making inferences about a drug’s pharmacological activity.
Drug Interactions: Competition for Binding Sites
 After IV drug administration, displacement of drugs from plasma
protein binding causing an increase in fu or increased free drug
concentration may potentially facilitate extravascular drug
distribution and an increase in the apparent volume of
distribution.
 The increased distribution results in a smaller Cp due to wider
distribution, making drug elimination more difficult (k = Cl/VD).
 This is analogous to reducing the fraction of free drug presented
for elimination per unit time based on a one-compartment model.
 Consequently, a longer t1/2 is expected due to wider tissue drug
distribution. The relationship is expressed by
in
order to assess the distribution effect due to protein binding.
Drug Interactions: Competition for Binding Sites
 Drug clearance may remain unaffected or only slightly changed as
the decrease in the elimination rate constant is compensated by an
increase in Vd .
 The mean steady-state total drug concentration will remain
unchanged based on no change in Cl or kVd.
 Whether the change in plasma drug–protein binding has
pharmacodynamic significance depends on whether the drug is
highly potent and has a narrow therapeutic window.
 Protein–drug binding has the buffering effect of preventing an
abrupt rise in free drug concentration in the body. For orally
administered drugs, the liver provides a good protection against
drug toxicity because of hepatic portal drug absorption and
metabolism.
 For a high E drug orally administered, an increase in fu causes ClH
to increase (i.e., fuClint), thus reducing total AUCoral but not changing
free drug AUCuoral due to the compensatory effect of fu AUCoral.
Drug Interactions
Changes in physiologic parameters (LBF, liver blood flow),Cl′int, fB,,
pharmacokinetic parameters(Cl, V, t1/2), and drug concentration and
effect (Css, Cssu, effect) for a low E drug (E<0.3) if Cl′int increases (indicated by arrow). An uptick in the line indicates an increase in the value of the parameter, while a downtick in the line indicates a decrease in the value of the parameter. Cl′int could increase due to a drug interaction that induces drug metabolizing enzymes. Drug Interactions- Protein Binding  As we saw, for a drug with a low hepatic extraction ratio, plasma protein–binding displacement drug interactions cause major pharmacokinetic alterations, but these interactions are not clinically significant because the pharmacologic effect of the drug does not change.  Because the clearance of the drug is dependent on the fu drug in the blood and Cl′int for a low hepatic extraction ratio agent, addition of a plasma protein–binding displacing compound will ↑Cl = ↑fB * Cl′int and ↑V = VB + [↑fB/fT]VT.  Because half-life depends on Cl and V, it is likely that because both increase, t1/2 will not substantially change (t1/2 = [0.693 • ↑V]/↑Cl).  However, it is possible that if either Cl or V of distribution changes disproportionately, t1/2 will change. Drug Interactions- Protein Binding  The total Css will decline because of the increase in Cl (↓Css = k0/↑Cl).However, the Cssu will remain unaltered because the fu of drug in the blood is higher than it was before the drug interaction occurred (Cssu = ↑fB *↓Css).  The pharmacologic effect of the drug does not change because the free concentration of drug in the blood is unchanged. An example of this drug interaction is the addition of diflunisal to patients stabilized on warfarin therapy.  Diflunisal displaces warfarin from plasma protein–binding sites but does not augment the anticoagulant effect of warfarin. If drug concentrations are available for the medication, it can be difficult to convince clinicians that a drug dosage increase is not needed even though total concentrations decline as a result of this interaction. When available, unbound drug concentrations can be used to document that no change in drug dosing is needed Drug Interactions- Protein Binding The valproic acid–phenytoin interaction involves displacement only. Although plasma protein binding of phenytoin is decreased when sodium valproate is administered chronically to a group of patients stabilized on phenytoin, with a resultant fall in the steady-state plasma phenytoin concentration, there was no substantial change in the unbound phenytoin concentration (colored).These observations are consistent with a displacement interaction of phenytoin by valproic acid. Note that the degree of phenytoin displacement depends on the dose of sodium valproate. Of the 25 patients stabilized on phenytoin, 11 received 900-mg sodium valproate/day; 9 received a 1350-mg/day; and some received both regimens. From: Mattson RH, Cramer JA, Williamson PD, Novelly, RA.Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol 1978;3:20–25.) Drug Interactions- Protein Binding When constantly infused, the unbound concentration (color) of a drug with a low extraction ratio remains virtually unchanged if a displacer with a long half-life, relative to the drug, is either infused or withdrawn. The change in total plasma drug concentration reflects the displacement Drug Interactions Changes in physiologic parameters (LBF, liver blood flow),Cl′int, fB,, pharmacokinetic parameters(Cl, V, t1/2), and drug concentration and effect (Css, Cssu, effect) for a high E (E>0.7) if Cl′int increases
(indicated by arrow). An uptick in the line indicates an increase in the
value of the parameter, while a downtick in the line indicates a
decrease in the value of the parameter. Cl′int could increase due to a
drug interaction that induces drug metabolizing enzymes.
Drug Interactions- Protein Binding
 For drugs with high E given i.v., plasma protein–binding
displacement drug interactions cause both major PK and PD
changes.
 Because the Cl of the drug is dependent solely on liver blood flow
for an agent of this type, total Cl does not change. However, both
volume of ↑V = VB + (↑fB/fT)VT] and ↑t1/2 will increase because of
plasma protein–binding displacement of the drug.
 Because total Cl did not change, the total Css remains unaltered.
However, Cssu (↑Cssu = ↑fB * Css) and pharmacologic effect
(↑effect ∝ ↑Cssu) of the drug will both increase.
 Currently, there are no clinically significant drug interactions of
this type. However, clinicians should be on the outlook for this
profile for highly protein-bound drugs with high hepatic extraction
ratios given i.v. because the interaction is very subtle.
 Most noteworthy is the fact that although total Css remain
unchanged, the pharmacologic effect of the drug is augmented. If
available, Cssu could be used to document the drug interaction.
Drug Interactions- Protein Binding
 If a drug with a high E is given orally, a plasma protein–binding
displacement drug interaction will cause a simultaneous increase
in the unbound fraction of drug in the blood (↑fB) and the hepatic
presystemic metabolism of the drug.
 Hepatic presystemic metabolism increases because the higher
unbound fraction of drug in the blood allows more drug molecules
to enter the liver where they are ultimately metabolized.
 The increase in hepatic presystemic metabolism leads to an
increased first-pass effect and decreased drug bioavailability (↓F).
 Total Css will be lower because of decreased drug bioavailability
[↓Css = (↓F[D/t])/Cl].
 However, the Cssu and pharmacologic effect remain unchanged
due to this type of drug interaction because the ↑fB is offset by the
decrease in the total Css (∼Cssu = ↑fB↓Css).
 Route of administration plays an important role in how important
plasma protein–binding displacement drug interactions are for
agents with high hepatic extraction ratios.
Drug Interactions- Protein Binding
Changes, at plateau, in the total( and ) and unbound ( ) concentrations (D =
displaced; C= control) depend on the extraction ratio of the drug and route of
drug administration. For a drug …
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