Protein Binding effect on PK

TEACHERS’ TOPICS

Role of Protein Binding in Pharmacokinetics

Reza Mehvar, PhD

School of Pharmacy, Texas Tech University Health Sciences Center

Submitted January 3, 2005; accepted February 13, 2005; published December 9, 2005.

This article describes the learning resources that are available to pharmacy students during a lecture on therole of protein binding in pharmacokinetics and pharmacodynamics as part of a clinical pharmacokineticscourse. The activities are designed to enable students to predict the effects of changes in the blood (orplasma) protein binding of drugs on kinetic parameters and to recommend dosage regimen modifications,if necessary. Using these resources, students realize that the effect of protein-binding alterations on drugclearance and volume of distribution is dependent on the extent of initial extraction ratio and volume ofdistribution of the drug, respectively. Further, they learn that the interpretation of the total drug concen-trations in blood or plasma in relation to the pharmacologic effects requires a clear understanding of thekinetics of the drug and the underlying physiologic changes leading to the altered protein binding.

Keywords: pharmacokinetics, volume of distribution, protein binding, free drug concentration, albumin, a1-acidglycoprotein

INTRODUCTIONProtein binding is covered in a 75-minute session in

theClinical Pharmacokinetics (Pharmacy 2340) course atTexas Tech. The course is offered during the fall semesterof the second year of the PharmD program. The detailsof the educational environment1 and the format2 of thecourse have been published recently. This article de-scribes the learning tools that this instructor uses to facil-itate student mastery of the role of protein binding inpharmacokinetics and pharmacodynamics.

General, ability-based outcomes for the session are:1. Predict the effects of alterations in the blood

(or plasma) protein binding of drugs on their ki-netic parameters and blood concentration-timecourses.

2. Recommend modifications in the dosageregimen based on the protein-binding–inducedchanges in the kinetic parameters of the drug.

The specific learning objectives of the sessionare for students to be able to answer the followingquestions:

1. What are the major plasma proteins? Which typeof drugs do they bind to?

2. What are the situations resulting in altered pro-tein binding?

3. What is the relationship between the free(unbound) and total (free plus bound) drug con-

centrations in blood (or plasma) for linear andnon-linear binding?

4. How does a change in the blood (or plasma) pro-tein binding affect the volume of distribution,clearance, and elimination half-life of drugs?

5. How does a change in the blood (or plasma)protein binding affect the steady-state concentra-tion of total and free drug?

6. How does the dosage regimen need to be modi-fied when the blood (or plasma) protein bindingof a drug changes?

SESSION CONTENTThe following material is provided online to students

as a reading assignment that must be completed beforeattending the class session for the discussion of the topic.Additionally, other readings from suggested textbooksserve as optional reading assignments. The equationsand a majority of the general concepts presented in thereading handout may be found in most pharmacokineticstextbooks.3-7

Total Versus Free (Unbound) Drug ConcentrationsIn addition to other components, the blood or plasma

contains proteins (P) such as albumin and a1-acid glyco-protein (AAG). Most drugs (D) in plasma are bound tothese proteins (DP) to some degree. As shown in Figure 1,the drug-protein interaction is reversible in that the drug-protein complex (DP) can dissociate and release the freedrug (Df).

In practice, what is usually measured as blood orplasma concentration of a drug is the total (bound1 free)

Corresponding Author: Reza Mehvar, PhD, School ofPharmacy, Texas Tech University Health Sciences Center,1300 S. Coulter, Amarillo, TX 79106. Tel: 806-356-4015, ext.337. FAX: 806-356-4034. E-mail: [email protected]

American Journal of Pharmaceutical Education 2005; 69 (5) Article 103.

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drug concentration in the sample. However, it is the freedrug (Df) that can pass the cell membranes and reach itssite of action; the drug-protein complex (DP) is too largeto pass through the membranes (Figure 1). Therefore, thefree drug is themoiety responsible for producing the phar-macologic effect. At equilibrium, the percent or fractionof the total drug bound to plasma proteins and red bloodcells remains constant for drugs with linear binding. Forexample, the degree of plasma protein binding of pheny-toin in adults is 90% or 0.90 (the percent or fractionunbound is 10% or 0.10). So, if the total plasma concen-tration of phenytoin is 20 mg/L, the free concentration is2 mg/L, and the bound concentration is 18 mg/L. Thisratio remains constant when the concentration is reducedto 15 mg/L: the free concentration is 1.5 mg/L and thebound concentration is 13.5 mg/L. Therefore, becausethe change in the free drug concentration (responsiblefor the pharmacologic effect) is proportional to that forthe total drug concentration, a measurement of the totaldrug concentration in practice can result in a predictionof the desired effects in most cases.

The problem arises, however, when a disease or coad-ministration of another drug would change the bindingequilibrium ratios. For instance, in patients with hypoal-buminemia, the degree of binding of phenytoin to albu-min is reduced. Therefore, the free fraction in this casewill be higher than normal. Consequently, a total plasmaconcentration of 20mg/L, which under normal conditionsresulted in a free concentration of 2 mg/L, would nowresult in a free concentration higher than 2 mg/L for thesepatients. This, however, will not be apparent by just mea-suring the total drug. Therefore, it is necessary to under-stand the effects of changes in the protein binding onvarious kinetic parameters and the total and free drugconcentrations in order to interpret the total plasma orblood concentrations and appropriately adjust the dosageregimen, if necessary.

Additionally, proteinbindingof somedrugs in thebloodor plasma may be nonlinear. This means that as the totalblood concentrations of the drug increase, the free fraction

also increases, resulting in amore than proportional increasein the free drug concentration at higher total drug concen-trations. In other words, at higher concentrations, the sitesresponsible for binding the drug are saturated, therefore,a greater proportion of the drug is in free form. One of theexamples of such drugs is disopyramide, which showshigher plasma free fractions at higher therapeutic concen-trations. For these drugs, interpretation of the total plasmaconcentration is extremely difficult. Therefore, experimen-tal measurement of free drug, as opposed to normally mea-sured total drug, may be necessary in these cases.

Major Plasma ProteinsAlbumin is the most important plasma protein with

a concentration of 3.5 to 5 g/dL (Table 1). Most acidic(anionic) drugs bind to plasma albumin. Some examplesinclude tolbutamide, phenytoin, ibuprofen, naproxen, andwarfarin. Albumin is synthesized in the liver. Therefore,the concentrations of albumin may be reduced in liverdiseases such as cirrhosis, resulting in changes in the pro-tein binding of the above drugs. Other diseases causing areduction in the plasma concentrations of albumin includeburns, surgery, acute viral hepatitis, renal failure, andmalnutrition. On the other hand, an increase in the plasmaconcentrations of albumin is observed in situations likedehydration and some neurological disorders. However,clinically, occurrence of hypoalbuminemia is much morefrequent than hyperalbuminemia.

In addition to the concentration, the affinity of albu-min to bind drugs can affect the degree of protein bindingof drugs. The affinity of albumin for binding drugs maybe decreased by some other drugs or in diseases, result-ing in higher free fractions in plasma.8 Additionally,drugs with higher affinity to albumin may displace drugswith lower affinity from their binding sites. For instance,salicylates are capable of displacing warfarin fromthe plasma albumin and increasing the free fraction ofwarfarin.

AAGhas amuch lower concentration (0.04-0.1 g/dL)than albumin and binds mostly to basic (cationic) andneutral drugs (Table 1). Similar to albumin, AAG is syn-thesized in the liver. Most drugs that bind to AAG alsobind to albumin. Examples of such drugs are propranolol,lidocaine, verapamil, disopyramide, and imipramine. Incontrast to albumin, clinical situations resulting in higherconcentrations of AAG are more frequent than thoseresulting in lower concentrations of this binding protein.The plasma concentrations of AAG are increased intrauma injuries, inflammatory diseases, surgery, burns,and acute myocardial infarction. Liver diseases such ascirrhosis would cause a reduction in the plasma concen-trations ofAAG. Similar to albumin, an apparent decrease

Figure 1. The pharmacokinetic model depicting theequilibrium between the free (Df) and protein-bound (DP)drug in blood and tissue. The model assumes that only the freedrug is subject to elimination and distribution into the tissues(including the site of action).


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in the affinity for binding to AAG can occur when onedrug displaces the other from its binding sites.

Lipoproteins, which consist of very low-density lip-oproteins, low-density lipoproteins, and high-densitylipoproteins, are synthesized in the liver and intestinalmucosa, and their normal plasma concentrations arevariable (,0.5 g/dL; Table 1). Usually, basic and neu-tral drugs with a high degree of lipophilicity are sub-stantially bound to lipoproteins. The concentrations oflipoproteins change in a variety of diseases such as renalfailure, diabetes mellitus, hyperlipoproteinemia, andalcoholism. Examples of drugs significantly binding to lip-oproteins are cyclosporine,9 tacrolimus,10 and propofol.11

Blood Versus PlasmaThe pharmacokinetic parameters of drugs are usually

estimated after measurement of drugs in plasma ratherthan whole blood. However, the relationships betweenmajor pharmacokinetic parameters (such as volume ofdistribution or clearance) and their physiological deter-minants (such as perfusion or protein binding) are basedon the value of these parameters in blood. If the blood:plasma concentration ratio of a drug is equal to 1, thekinetic parameters obtained using the plasma and bloodwill be identical. Additionally, for drugs with a blood toplasma ratio different than 1, the plasma concentrationsmay be easily converted to the respective blood values ifthe blood to plasma ratio is known. Unfortunately, mostreports in the literature use blood and plasma kineticvalues interchangeably, even if it is not shown that theblood to plasma ratio is equal to 1. In the followingsection, we will base our discussion on blood data andprovide alternative relationships, if they exist, for theplasma data. For simplicity, when literature examplesare used to demonstrate concepts, we assume a bloodto plasma ratio of 1.

How Does Protein Binding Affect MajorPharmacokinetic Parameters?

Volume of distribution. The volume of distributionat steady state (VSS) may be defined by the followingequation3:

VSS 5VB1fubfut

� �VT ð1Þ

where VB and VT are the volume of blood and tissue(extravascular space), and fub and fut are the unboundfractions in the blood and tissue, respectively. VB is~0.07 L/kg or 5 L/70 kg. VT is the real extravascularvolume in which the drug is distributed. For lipophilic(non-polar) drugs, VT (~0.6 L/kg) is the total body waterminus the blood water volume, because these drugs dis-tribute to both the extracellular and intracellular spaces.The value of VT for hydrophilic (polar) drugs that do notpenetrate intracellular space is the volume of extracellularwater minus the plasma water volume (~0.13 L/kg).5

As mentioned above, the concentrations of drugs aremostly measured in plasma (instead of whole blood), andfree fractions are also estimated in plasma (fup). However,if the blood:plasma concentration ratio of the drug isknown, fub may be easily estimated from fup and bloodto plasma ratio as demonstrated below:

fub 5fupB :P

ð2Þ

In the absence of blood to plasma ratio, another pa-rameter, VSS based on the plasma data (V9SS), may beestimated using the following equation:

V 0SS 5VP1

fupfut

� �V 0T ð3Þ

where V9SS is a proportionality constant relating theamount of drug in the body to the plasma concentrations(as opposed to blood concentration for VSS). V9T is differ-ent fromVT in that it also contains the volumeof red bloodcells in addition to the extravascular space.3 For drugs thatare restricted to plasma (such as macromolecules), VP isequal to the volume of plasma (~3 L/70 kg). However,because plasma proteins such as albumin enter slowly intothe interstitial fluid, at equilibrium VP may be larger thanthe volume of plasma (~7 L/70 kg or 0.10 L/kg) for smallmolecule drugs.4

As one may recognize from the above equations, VSS

may differ significantly from V9SS. However, most inves-tigators use these 2 terms interchangeably, which is cor-rect only if the blood to plasma ratio is equal to unity.

Conceptually, these equations predict a larger VSS (orV9SS) if fub (or fup) is increased and a lowerVSS (orV9SS) iffut is increased. This is understandable because a higherfree fraction in blood/plasma results in a movement of the

Table 1. Major Drug Binding Proteins in Plasma4,7

Normal ConcentrationProtein MW, g/mole g/dL mM Type of Drugs Bound Example

Albumin 67,000 3.5-5 500-700 acidic, basic Warfarin

a1-Acid glycoprotein 42,000 0.04-0.1 9-23 basic, neutral Propranolol

Lipoproteins 200,000-2,400,000 Varies Varies lipophilic basic and neutral Cyclosporine


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free drug from blood/plasma to the tissues and an increasein the distribution of the drug. On the other hand, a higherfree fraction in the tissue would result in a movement ofthe drug from the tissue to blood/plasma and a reductionin the volume of distribution. The magnitude of theincreases or decreases in VSS (or V9SS), however, dependson the original VSS (or V9SS).

At one extreme, a drug with a very low VSS (or V9SS)will have a VSS (or V9SS) almost equal to VB (or VP),meaning that the drug does not distribute much into thetissues. For these drugs, the above equations may be sim-plified as:

VSS � VB ð4Þ

V 0SS � VP ð5Þ

Therefore, changes in the blood/plasma or tissuebinding (fub/fup or fut) would not significantly affectthe VSS (or V9SS) of these drugs. Examples of suchdrugs are chlorpropamide (V9SS of 0.097 L/kg), tolbu-tamide (V9SS of ~0.1 L/kg), and dicloxacillin (V9SS of0.086 L/kg).12

At the other extreme, for drugs with very large VSS

(or V9SS), the value of VB (or VP) is relatively insignifi-cant, and the above equation may be rewritten as:

VSS �fubfut

� �VT ð6Þ

V 0SS �

fupfut

� �V 0T ð7Þ

Therefore, changes in the values of fub/fup or fut wouldaffect the value of VSS (or V9SS) almost proportionally.Examples of such drugs are propranolol (VSS of 4.3 L/kg)and amitriptyline (VSS of 15 L/kg).12 Most drugs, how-ever, fall in between these 2 categories; thus, their VSS

is affected to some degree (less than proportional) bychanges in fub and/or fut. In conclusion, the effect ofchanges in fub or fut on VSS depends on the initial extentof the distribution of the drug.

Clearance. Basedon thewell-stirredmodel of hepaticmetabolism, the hepatic clearance (Clh) is related to hep-atic extraction ratio (E) and its components fub, intrinsicclearance of the free drug (Cl9int), and liver blood flow (Q)according to the following equation:4

Clh 5Q � E5Qfub � Cl0int

Q1 fub � Cl0intð8Þ

According to the above equation, drugs with a high E(close to 1) have a high clearance close to the hepaticblood flow, whereas drugs with a low E (E close to zero)

have a low Cl significantly less than the hepatic bloodflow. For these 2 extreme cases of very low and very highE (or Cl) drugs, the above equation may be simplified:

Cl � fub � Cl0int; for low E or low Cl ð9Þ

Cl � Q; for high E or high Cl ð10Þ

Therefore, a change in fub for the low E (or low Cl)drugs would directly affect their Clh. Examples of drugswith lowE (or lowCl) are phenytoin, diazepam, warfarin,and valproic acid. On the other hand, a change in the fub ofhigh E (high Cl) drugs would not have any effect on theirCl. Examples of high E (high Cl) drugs are tricyclic anti-depressants, verapamil, and propranolol.

In contrast to all or none effects for high and low Cldrugs, a change in the fub of a drugwith an intermediate Clor E would have some effect on its clearance. However,the change in clearance will not be proportional to thechange in fub.

The effect of fub on the renal clearance of drugs is alsosimilar to those explained for hepatic clearance in that thedrugs with low renal E are affected most and those withhigh renal E are affected least by changes in fub. Examplesof high and low renal E drugs are penicillins and genta-micin, respectively.

In conclusion, the effect of changes in fub of drugs ontheir clearance is dependent on the initial clearance or Eof the drug.

Half-life. The elimination half-life is not an inde-pendent parameter and only reflects the magnitude ofdistribution and elimination.1 The half-life is dependenton both V and Cl as defined below:

t1=2 50:693V

Clð11Þ

Therefore, the effect of changes in fub of drugs ontheir half-life is dependent on the changes in V and/orCl induced by the alterations in protein binding.

The Case for Four Extreme ScenariosAs examples of the effects of protein binding on the

kinetics and dosage requirement of drugs, let us considerthe following four scenarios.

Drugs with high clearance and large volume ofdistribution. Because the clearance of these drugs ismostly controlled by the blood flow (Cl 5 Q), a changein fub is not expected to affect the clearance of these drugs.On the other hand, the VSS of large volume drugs arealmost proportional to the free fraction of the drug inblood (VSS � [(fub/fut) 3 VT]). Therefore, an increase inthe blood free fraction, for example, would result in analmost proportional increase in the VSS of these drugs.


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Consequently, the half-life will be prolonged pro-portionally. Because the clearance does not change(4), the total average steady state concentration(C‘

ave) after intravenous administration remains thesame (4):

4C‘ave 5

Dose=t

4Clð12Þ

Consequently, based on the total concentrations,one may assume that no adjustment in dosing rateis necessary. However, because the free fraction ofthe drug in blood is increased ([), the average steadystate concentration of the free drug (C‘

ave,free) willbe increased ([), which may result in toxicity oradverse effects despite apparently ‘‘normal’’ totalblood values.

[C‘ave; free 5C‘

ave43[fub ð13Þ

For these drugs, therefore, a change in the free frac-tion in bloodmay require adjustment of the dosing rate (inthis case, a reduction).

An example of such drugs is propranolol with VSS of4.3 L/kg, Cl of 16 mL/min/kg, and fup of 0.13, respec-tively.12 Patients with acute myocardial infarction havehigher AAG concentrations in plasma.13 Therefore, thefree fraction of propranolol in plasma of these patientsdecreases.13 Because of its high E, however, the clearanceand consequently the steady state total concentration ofintravenous propranolol are not expected to change inthese patients. On the other hand, the lower free fractionis anticipated to cause a reduction in the free concentra-tions and pharmacologic effects of the drug in patientswith acutemyocardial infarction. Indeed, higher than nor-mal dosing rates of propranolol may be required inpatients with established infarction.5

Drugs with low clearance and small volume ofdistribution. For drugs with low clearance and smallvolume of distribution, clearance is proportional to thefree blood fraction (Cl � fub 3 Cl9int). Therefore, achange in the free fraction is almost proportionallyreflected in the clearance of the drug. On the other hand,the VSS of these drugs is not sensitive to changes in thefree fractions (VSS � VB). Consequently, the half-lifewill increase if fub is decreased (Cl is decreased), and itwill decrease if fub is increased (Cl is increased). Achange in clearance would result in an inverse changein the total average steady state concentration. However,this change is not expected to affect the pharmacologiceffects of the drug because the free average steady stateconcentration is expected to remain the same. Therefore,the dosing rate generally does not have to be changed forthese drugs.

An example of such drugs is warfarin with V9SS of0.14 L/kg, clearance of 0.045 mL/min/kg, and fup of0.01.12 Trichloroacetic acid, a metabolite of chloralhydrate, is known to displace warfarin from its bindingsite in plasma, thereby increasing its fup.

14 Consequently,the clearance of warfarin increases almost proportionallyto the increase in fup, and its half-life decreases. At equi-librium, the total average steady state concentration ofwarfarin in this interaction decreases, whereas the freeconcentration remains the same. Therefore, in the longterm, the pharmacologic effect remains the same and nodosage adjustment is necessary.14 However, becausewar-farin has a narrow therapeutic range, the initial increase infup before equilibrium (reduction of total plasma concen-trations) may result in a significant increase in the freedrug concentration and pharmacologic effect. Therefore,a temporary reduction in dosing rate may be necessary.

Drugs with low clearance and large volume ofdistribution. Both the clearance and VSS of drugs withlow clearance and large volume of distribution are verysensitive to the changes in fub. However, the half-liferemains almost constant because the effects of changesin the clearance and VSS on the half-life are cancelled out.Similar to the above case, the change in the clearanceresults in a change in the total drug concentration. How-ever, the average free drug concentration remains thesame. Therefore, there is no need for an adjustment inthe dosing rate.

Diazepam is an example for this group.Diazepam hasa V9SS of 1.1 L/kg, clearance of 0.38 mL/min/kg, and fupof 0.013.12 Situations resulting in an increase in fup of thedrug (eg, hypoalbuminemia) are expected to increase boththe V9SS and clearance of the drug (with no significantchange in half-life). However, no change in the pharma-cologic effect is expected.

Drugs with high clearance and small volume ofdistribution. A change in blood protein binding is notexpected to substantially affect the clearance, VSS, orhalf-life of these drugs. Therefore, the total blood concen-trations are expected to remain the same in the presence ofaltered protein binding. However, the free drug concen-trationswill change proportional to the changes in the freefraction in blood. Therefore, the dosing rate of these drugsneeds to be altered despite a ‘‘normal’’ blood concentra-tion of the total drug.

Penicillins belong to this category of drugs. Salicy-lates increase the free fraction of penicillins without caus-ing any change in their clearance or total concentration.15

Although the plasma concentration of the free drugincreases in these situations, in practice, no dosage adjust-ment is carried out. This is because of the high therapeuticindex and relative safety of these drugs.


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Summary of Pharmacokinetic ChangesTable 2 demonstrates the effects of changes in the

binding of drugs in blood on various pharmacokineticparameters, blood concentrations of the free and totaldrug, and the need for an adjustment in the dosing rateof drug. As demonstrated in the Table, a change in thebinding of drugs in blood does not generally require analteration in the dosing rate for low clearance drugs. Incontrast, alterations in protein binding require dosageadjustment in the case of highly cleared drugs. Pharma-cokinetic-based design of dosage regimens (dose anddosage interval) and its adjustment in the presence ofalterations in the pharmacokinetic parameters16 are thesubject of a separate topic in this course.

Implications of Protein Binding in TherapeuticDrug Monitoring

An example of applying the above concepts in a clin-ical setting is the reduction in the plasma protein bindingof phenytoin in the presence of renal disease. The fup ofphenytoin is around 0.1.12 The therapeutic range of thetotal drug in plasma is between 10 mg/L to 20 mg/L,resulting in an estimated free concentration range of1-2 mg/L. Let us assume that with the administration ofa daily dose of 400mg phenytoin, the average steady stateplasma concentration of the total drug is 15 mg/L. Thismeans that the free drug concentration is 1.5 (15 3 0.1)mg/L. In renal failure, the fup of phenytoin is increased bya factor of 2 to 3.17 Let us assume that the fup in renalfailure is 0.2. Phenytoin is a drug with a very low clear-ance. Therefore, a twofold increase in the fup of the drugwould result in an almost proportional increase in itsplasma Cl. Consequently, the average concentration ofthe total drug at steady state would decrease by a factorof 2 to a value of 7.5 mg/L. This concentration may beregarded as subtherapeutic because the normal range iswithin 10-20mg/L.However, amore careful examination

of the data indicates that the concentration of the free drug(responsible for the pharmacologic effect) in the renalfailure patient (7.5 3 0.2 5 1.5 mg/L) is the same asthat in the normal patient (153 0.1 5 1.5 mg/L). There-fore, despite lower total concentrations of phenytoin, noadjustment in the dosing rate of the drug is necessary.However, the maximum and minimum concentrations(and fluctuation between them) are affected by thechanges in the half-life. Therefore, if the half-life is sig-nificantly decreased, the fluctuation may be outside thetherapeutic range (despite the acceptable average concen-tration). Consequently, dose and dosage intervals mayneed adjustments (lower doses given more frequently).In this particular case, normally no adjustment is neededin renal disease. This is because an increase in fup is alsoexpected to almost proportionally increase the VSS ofphenytoin, which is relatively large (~50 L). Therefore,a simultaneous increase in Cl and V is expected to resultin minimal changes in the half-life.

For drugs substantially bound to plasma albumin, suchas phenytoin, the total plasma concentrations in hypoalbu-minemic patients may be adjusted based on the degree ofdecrease in the albumin level, before making a therapeuticjudgment. The adjusted plasma concentration (CAdjusted)may be obtained from the observed plasma concentrationof the drug (CObserved), free fraction of the drug in subjectswith normal albumin levels (fup) and the protein (albumin)concentrations in normal subjects (PNormal) and the hypo-albuminemic patient (PHypoalbumin):

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CAdjusted 5CObserved

(12 fup) 3PHypoalbumin

PNormal

� �1 fup

ð14Þ

Substituting for PNormal (4.4 g/dL) and fup (0.1 forphenytoin), the following equation may be used for

Table 2. Summary of Changes in the Pharmacokinetic Parameters and Steady-State Blood Concentrations of the Free andTotal Drug and the Need For Dosing Rate Adjustment in the Presence of Altered Free Fraction in Blood*

Drug fub VSS Cl t1/2 CSS,TOTAL CSS,FREE Dosing Rate

High Cl-High V [ [ 4 [ 4 [ Y

Y Y 4 Y 4 Y [

Low Cl-Low V [ 4 [ Y Y 4 4

Y 4 Y [ [ 4 4

Low Cl-High V [ [ [ 4 Y 4 4

Y Y Y 4 [ 4 4

High Cl-Low V [ 4 4 4 4 [ Y

Y 4 4 4 4 Y [

*fub: free fraction in blood; VSS: volume of distribution at steady state; Cl: clearance; t1/2: elimination half-life; CSS,TOTAL: steady-stateconcentration of total drug; CSS,FREE: steady-state concentration of free drug


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phenytoin:

CAdjusted 5CObserved

0:9 3PHypoalbumin

4:4

� �1 0:1

ð15Þ

Example. A patient with an albumin level of 2 g/dLhas an average plasma phenytoin concentration of 6 mg/L.Not considering the patient’s low albumin level, onemight conclude that the phenytoin concentration in thispatient is subtherapeutic. However, calculation of ad-justed concentration shows a value of 11.8 mg/L, whichis within the therapeutic range:

CAdjusted 56mg=L

0:932 g=dL

4:4 g=dL

� �1 0:1

5 11:8mg=L ð16Þ

The adjusted concentration of 11.8 mg/L means thatan observed concentration of 6 mg/L in this hypoalbumi-nemic patient is equivalent to a concentration of 11.8mg/Lin a patient with normal albumin concentration (in termsof free drug concentration and pharmacologic effect).

PRACTICE PROBLEM, QUIZ, ANDASSIGNMENT

In addition to the reading handout discussed above, thestudents are given a practice problem (Appendix 1) ahead ofthe scheduled session. Students are expected to work on theproblem before attending the class, consulting the readingnote. After a brief introduction of the topic by the instructor,most of the class time is devoted to both students and theinstructor discussing the solution to the practice problem.

During the last 10 minutes of the 75-minute session,students take an online quiz18 consisting of questionsrelated to the topic of protein binding covered duringthe session. Finally, students are required to submit anindividualized, online assignment19 by the end of theday the session is held.

REFERENCES1. Mehvar R. The relationship among pharmacokinetic parameters:effects of altered kinetics on the drug plasma concentration-timeprofiles. Am J Pharm Educ. 2004;68:Article 36.2. Mehvar R. Development and evaluation of a quasi problem-based,objective-driven learning strategy in introductory and clinicalpharmacokinetics courses. J Pharm Teaching. 1999;7:17-29.

3. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY:Marcel Dekker; 1982:199-219.4. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts andApplications. 3rd ed. Philadelphia, Pa: Williams &Wilkins;1995:137-55.5. MacKichan JJ. Influence of protein binding and use of unbound(free) drug concentration. In: Evans WE, Schentag JJ, Jusko WJ, eds.Applied Pharmacokinetics: Principles of Therapeutic DrugMonitoring. 3rd ed. Vancouver, Wash: Applied Therapeutics, Inc.;1992:5-1-5-48.6. Winter ME. Basic Clinical Pharmacokinetics. 4th ed. Philadelphia,Pa: Lippincott Williams & Wilkins; 2003:10-8.7. DiPiro J, Spruill W, Blouin R, Pruemer J. Concepts in ClinicalPharmacokinetics. 3rd ed. Bethesda, Md: American Society ofHealth-System Pharmacists; 2002:113-25.8. Koyama H, Sugioka N, Uno A, Mori S, Nakajima K. Effect ofglycosylation on carbamazepine-serum protein binding inhumans. J Clin Pharmacol. 1997;37:1048-55.9. Akhlaghi F, Trull AK. Distribution of cyclosporin in organtransplant recipients. Clin Pharmacokinet. 2002;41:615-37.10. Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ.Changes in tacrolimus distribution in blood and plasma proteinbinding following liver transplantation. Ther Drug Monit.2004;26:506-15.11. de la Fuente L, Lukas JC, Vazquez JA, Jauregizar N,Calvo R, Suarez E. ‘In vitro’ binding of propofol to serumlipoproteins in thyroid dysfunction. Eur J Clin Pharmacol.2002;58:615-9.12. Thummel KE, Shen DD. Design and optimization of dosageregimens: pharmacokinetic data. In: Hardman JG, Limbird LE,Goodman Gilman A, eds. Goodman & Gilman’s ThePharmacological Basis of Therapeutics. 10th ed. New York, NY:McGraw-Hill; 2001:1917-2023.13. Paxton JW, Norris RM. Propranolol disposition afteracute myocardial infarction. Clin Pharmacol Ther. 1984;36:337-42.14. MacKichan JJ. Pharmacokinetic consequences of drugdisplacement from blood and tissue proteins. Clin Pharmacokinet.1984;9:32-41.15. Kunin CM. Clinical pharmacology of the new penicillins. II.Effect of drugs which interfere with binding to serumproteins. Clin Pharmacol Ther. 1966;7:180-8.16. Mehvar R. Pharmacokinetic-based design and modification ofdosage regimens. Am J Pharm Educ. 1998;62:189-95.17. Odar-Cederlof I, Borga O. Kinetics of diphenylhydantoin inuraemic patients: consequences of decreased plasma proteinbinding. Eur J Clin Pharmacol. 1974;7:31-7.18. Mehvar R. Creation of a dynamic question database forpharmacokinetics. Am J Pharm Educ. 2000;64:441-5.19. Mehvar R. On-line, individualized, and interactivepharmacokinetic scenarios with immediate grading and feedbackand potential for use by multiple instructors. Am J Pharm Educ.1999;63:348-53.


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Appendix 1. Practice Problem

Tolbutamide is a weakly acidic drug that is almostcompletely eliminated by hepatic metabolism. The drughas a volume of distribution (V) of 0.10 L/kg, clearance(Cl) of 0.24mL/min/kg, and an unbound fraction (plasma;fup) of 0.04 in healthy volunteers. In patients with acuteviral hepatitis, the fup of tolbutamide increases.

1. What is the main plasma protein responsible forbinding to tolbutamide? What are the diseasestates/drugs that affect the extent and/or affinityof binding of this protein to drugs like tolbuta-mide?

2. How is the binding of a weakly basic or neutraldrug different from that of tolbutamide?

3. How would you characterize tolbutamide interms of its extent of Cl and V?

4. Predict the changes in the kinetic parameters (Cl,V, t1/2) of tolbutamide in acute viral hepatitis.

5. Predict the changes in the average steady-stateconcentration of tolbutamide (both total and freedrug) as a result of the disease.

6. How should the dosage regimen be different, ifany, in patients with acute viral hepatitis com-pared with patients without this disease?

Instructions: For simplicity, assume a blood:plasmaratio of 1 and a twofold increase in fup in acute viralhepatitis. Also, please use an average blood flow of1500 mL/min in a 70-kg subject for your calculations.


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Protein Binding effect on PK

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