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Pharmacokinetic-pharmacodynamic relationshipJd Baggot

To cite this version:Jd Baggot. Pharmacokinetic-pharmacodynamic relationship. Annales de Recherches Vétérinaires,INRA Editions, 1990, 21 (suppl1), pp.29s-40s. �hal-00901990�

Pharmacokinetic-pharmacodynamic relationship

JD Baggot

Irish Equine Centre, Johnstown, County Kildare, Ireland

(Pharmacokinetics of Veterinary Drugs. 11-12 October 1989, Foug6res, France)

Summary― The dose-effect relationship can be determined by linking pharmacokinetic drug be-havior with information on pharmacodynamic activity. This requires that the quantifiable concentra-tions of drug (or metabolites) in the plasma (systemic circulation) are related to the concentration atthe site of action. Using the pharmacokinetic parameters and a pharmacokinetic-pharmacodynamicmodel, it is possible to predict the pharmacodynamic response to certain drugs; this provides usefulinformation for understanding drug action and to determine dosage regimen.

pharmacokinetic-pharmacodynamic model

Résumé― Relations pharmacocinétiques-pharmacodynamiques. Les relations dose!ffetpeu-vent être déterminées en reliant le comportement pharmacocinétique d’un principe actif à l’activitépharmacodynamique. Celà requiert que les concentrations mesurables dans le plasma soient corré-lées avec les concentrations au site d’action. En utilisant les paramètres pharmacocinétiques et unmodèle pharmacocinétique!harmacodynamique, il est possible, pour certains médicaments, deprédire la réponse pharmacodynamique. Cela donne des informations utiles pour comprendre l’ac-tion d’un principe actif et pour déterminer les posologies.

modèle pharmacocinétique-pharmacodynamique

INTRODUCTION

The relationship between the dose of adrug and the clinically observed pharma-cological effect may be quite complex. Anunderstanding of the dose-effect relation-ship can generally be obtained by linkingpharmacokinetic behavior with informationon pharmacodynamic activity. Pharmacok-inetics defines the mathematical relation-

ship that exists between the dose of a

drug and the plasma concentration-timeprofile of the drug. Pharmacodynamics ex-tends this relationship to the correlationbetween plasma drug concentrations andthe pharmacological effect. The intensityof the pharmacological effect generally de-termines whether the desired clinical ef-fect or a toxic effect is produced. An inher-ent assumption is that the quantifiableconcentrations of drug in the plasma (sys-temic circulation) are related to the con-centrations at the site of action.

The clinical utility of pharmacokineticsrelies on the premise that a therapeuticrange of plasma concentrations can be de-fined for each drug. The width of this

range reflects the relative safety of the

drug and, together with half-life, influencesthe dosing interval. Metabolites may haveto be considered when they possess phar-macological activity that contributes to thetherapeutic or toxic effect. For drugs with anarrow margin of safety or antimicrobialagents that can rapidly induce bacterial re-sistance, the clinician must weigh the ad-verse potential of the dosage regimen andduration of treatment against effectivenessin treating the disease condition. Since an-timicrobial agents do not produce phar-macological effects at usual dosage, anyrange of plasma concentrations defined re-lates to quantitative susceptibility (MIC val-ue, determined in vitro) of pathogenic mi-croorganisms and the induction of an

undesirable pharmacological (toxic) effect.The latter may often be related to the dura-tion of antimicrobial therapy rather thanthe peak plasma concentration attained atusual dosage. Since dosage regimens aregenerally based on pharmacokinetic pa-rameters, it is relevant to distinguish be-tween pharmacological and antimicrobial

agents with regard to the definition of ther-apeutic plasma concentrations.

THERAPEUTIC CONCENTRATIONS

For many pharmacological agents, the

therapeutic range of plasma concentra-

tions has been defined (table I). It is as-sumed that the plasma drug concentrationrange defined in humans is applicable todomestic animals. On this basis, the dos-ing rate of a drug that will produce similarpharmacological effects in different spe-cies can be calculated. This concept hasbeen established for a variety of drugs. Forexample, to produce a sustained bron-chodilator effect with theophylline (phos-phodiesterase inhibitor), an averagesteady-state plasma concentration of 10

,ug/ml is required. Based on the therapeuticrange of plasma concentrations and takinginto account the systemic availability (F)and clearance (CI) of theophylline, oral

dosage regimens for aminophylline can becalculated. The dosing rates that will pro-duce equivalent bronchodilator effects inhorses or cats (5 mg/kg at 12 h intervals)and in dogs (10 mg/kg at 8 h intervals) aredistinctly different.

For drugs that produce pharmacologicaleffects at very low plasma concentrations(such as reserpine) the limit of assay sen-sitivity may not allow therapeutic plasmaconcentrations to be defined or the rela-

tionship between plasma concentrations

and pharmacological effect to be estab-

lished.

The clinical effectiveness of a drugproduct can be influenced by the dosingrate, which can be defined as the systemi-cally available dose/unit time:

Fx dose

dosing rate =dosing interval

where F is the fraction of the dose whichenters the systemic circulation unchanged.In addition, formulation of the dosage formand route of administration may affect the

efficacy and safety of the drug. These fac-tors collectively contribute to the plasmaconcentration-time profile.

APPROACH TO PHARMACODYNAMICS

Pharmacodynamics is the study of the re-lationship between the concentration of adrug at the site of action (biophase con-centration) and the resultant pharmacologi-cal effects. Since it is seldom possible tomeasure the biophase drug concentration,pharmacodynamic analyses frequently re-quire making the assumption that the con-centration in the plasma is related to theconcentration at the receptor site. Thus, bycombining the plasma concentration-timeprofile with some quantifiable measure ofdrug response in pharmacodynamic mod-els, an understanding of the concentra-

tion-effect relationship can be obtained.Studies of plasma concentration-effect re-lationships may provide information on thecontribution of species variations in recep-

tor sensitivity to observed differences in

pharmacological response.In selecting a model to analyze the rela-

tionship between plasma concentrationand pharmacological effect of a drug, theforemost consideration is the character of

the particular response (Schwinghammerand Kroboth, 1988). Before an appropriatepharmacodynamic model can be selected,effect versus time plots of the data from

each individual animal in the experimentalgroup should be examined visually to ob-tain information about the dose-responserelationship, the time course of effect afterdifferent doses and the behavior of the

physiological system of interest in the ab-sence of drug, such as after placebo ad-ministration. An examination of individualanimal plots of pharmacological effect ver-sus plasma drug concentration will assistin the selection of a model. Such plots mayreveal important characteristics of the ef-fect-concentration relationship, such as

linearity, the maximum achievable effect,development of tolerance, a lag betweenpeak concentration and peak effect, andthe degree of individual variation in re-

sponse.

Although the plasma concentration-effect relationship has been described forcertain drug classes (anti-arrhythmics, his-tamine H2-receptor antagonists, cardiac

glycosides, neuromuscular blocking drugs),pharmacodynamic modelling is empirical.To gain a more complete understanding ofthe dose-plasma concentration-effect re-

lationship, the use of combined pharma-cokinetic-pharmacodynamic models that

incorporate an effect compartment may benecessary.

SPECIES DIFFERENCES IN DOSAGE

Appropriate dosage for different speciestakes into account species variations in

both the pharmacokinetic behavior and

pharmacodynamic activity of the drug. Therequirement for species differences indose level may be attributed to variationsin systemic availability (extent of absorp-tion), particularly from the gastrointestinaltract, or the distribution of the drug, or maybe due to differences in the sensitivity ofdrug receptor sites. The low dose levels,relative to those for dogs, of morphine forcats and xylazine for cattle may be due tohigher sensitivity of receptor sites for thesedrugs in the central nervous system (phar-macodynamic variation). The wide speciesvariations in dose level and sensitivity tothe neuromuscular blocking effect of succi-nylcholine has been attributed to differenc-es in activity of plasma pseudocholines-terase. This source of variation could beconsidered to have a pharmacokineticrather than pharmacodynamic basis, sinceit is metabolism of the drug that accountsfor the species differences. The majority ofspecies differences in pharmacological ef-fects that result from fixed dosage of adrug is due to variations in pharmacokinet-ic processes, principally the rate of hepaticmicrosomal metabolism (oxidative reac-

tions and glucuronide synthesis). Thesedifferences can be accommodated by ad-justing the dosing interval, for example,the dosing interval for aspirin in cats is 48h compared with 12 h in dogs, since thecat has a relative deficiency in glucuronyltransferase activity.

In the various species of laboratory ani-mals, drugs are generally eliminated morerapidly than in domestic animals due to thehigher rate of basic metabolism in the for-mer. Since basic metabolism of warm-

blooded animals is a function of body sur-face area rather than body weight, smallanimal species require higher doses of

drugs and shorter dosing intervals than

larger species. Extrapolation of pharmaco-logical and toxicological data based onmetabolic weight (Wbldyo .756) appears to

apply within the group of ruminant animalsand monogastric herbivores as well as

from one carnivorous species to another(van Miert, 1989). When wide variations inresponse are observed in some animal

species, with no relationship to animal

size, interspecies predictions on the dose-response relationship are unlikely to bevalid.

The metabolism rate of some drugs is

dose-dependent in certain species at doselevels above a certain limit. The dose levelat which a major elimination pathway for adrug becomes capacity limited determinesthe clinical significance of dose-dependentelimination. Unless dose-dependent elimi-nation is a feature of therapeutic dosage,as is the case with phenylbutazone andphenytoin, this limitation in capacity to

eliminate a drug is relatively unimportant.

PHARMACOKINETIC PARAMETERS

Pharmacokinetic parameters describe drugabsorption and disposition processes in

quantitative terms and provide a basis forcalculation of dosage regimens.

The basic pharmacokinetic parametersare clearance (CI), which measures theability of the body to eliminate the drug,and volume of distribution (Vd), whichquantifies the apparent space available, inboth the systemic circulation and the tis-sues of distribution, to contain the drug.Another important parameter is systemicavailability (F) (extent of absorption), whichexpresses the fraction of the dose that en-ters the systemic circulation unchangedfollowing parenteral (non-vascular) or oraladministration.

Clearance

The systemic clearance of a drug reflectsthe sum of the clearances from all individu-

al organs that play a role in eliminating thedrug. It can be calculated by dividing thesystemically available dose by the area un-der the plasma concentration-time curve(AUC):

The AUC can be calculated either as the

integral of the equation describing the plas-ma concentration-time curve or by the

trapezoidal rule, using the measured plas-ma concentrations at the blood samplingtimes (Baggot, 1977). It is only when thedrug is administered intravenously that thedose can be assumed to be completelyavailable systemically.

The calculation of clearance, based onarea under the curve measurements, of

drugs that follow first-order kinetics is inde-pendent of the number of compartments ina pharmacokinetic model. The clearanceof most drugs is constant at the concentra-tions encountered clinically, since their

elimination obeys first-order kinetics. For

drugs that exhibit saturable or dose-

dependent elimination, clearance will varydepending upon the plasma concentrationachieved. It should be noted that whenblood (rather than plasma) concentration isused to define clearance, the maximum

clearance possible is equal to the sum ofblood flows to the various organs of elimi-nation (liver, kidney, lung and other tissuesin which elimination processes occur).

Clearance is probably the most impor-tant pharmacokinetic parameter to consid-er in designing drug dosage regimens.

Species variations in clearance and chang-es induced by the presence of disease

conditions or in certain physiological statescan be attributed to differences in activityof the elimination processes for the drug.Allowance for species variations or chang-es in clearance can be made by appropri-ate adjustment of the dosing rate. The pre-vailing assumption is that plasmaconcentrations within the usual therapeuticrange will produce an equivalent pharmac-ological response in terms of drug efficacyand safety (that is, pharmacodynamic ac-tivity is assumed to remain unchanged).

In drug therapy, the objective of the dos-age regimen is to maintain plasma concen-trations within the therapeutic concentra-tion range. The steady-state plasmaconcentration (Cp!ss!) attained by continu-ous infusion or the average plasma levelfollowing multiple dosing (repeated admin-istration of a fixed dose at a constant dos-

ing interval) depends upon systemic clear-ance:

The time required to reach steady state orto change from one steady-state concen-tration to another depends solely upon thehalf-life of the drug. Knowledge of the plas-ma concentrations that are associated with

therapeutic effects and of certain pharma-cokinetic parameters is required in design-ing the dosing rate. Otherwise, dosage hasto be based on experience with use of thedrug and clinical assessment of the phar-macological effects produced.

Although clearance describes drug elim-ination from the body, it is expressed in

units of flow rather than time (as in half-

life). This implies that clearance is a poorindicator of drug persistence in the body.

Volume of distribution

The volume of distribution, which relatesthe amount of drug in the body to the con-centration in the plasma, provides an esti-mate of the extent of distibution (ratherthan describing the distribution pattern) ofthe drug. This parameter (volume term)can be calculated from the equation:

where /3 is the overall elimination rate con-stant of the drug, determined from theelimination phase of the disposition curve.

Volume of distribution is determined bycertain physicochemical properties (pKaand lipid solubility) of the drug and the de-gree of binding to plasma proteins and ex-travascular tissues. This volume term can

vary among species due to differences inbody composition, particularly anatomicalfeatures of the gastrointestinal tract. Drugsthat are relatively polar (penicillins, cepha-losporins, aminoglycosides, non-steroidal

anti-inflammatory drugs) may have vol-umes of distribution similar to the extracel-lular fluid volume (200-300 ml/kg). It must

be emphasized, however, that the volumeof distribution does not relate to a physio-logical space and its magnitude cannot beused to predict the distribution pattern of adrug. Some lipid-soluble organic bases

(clonidine, propranolol and morphine)are effective at low plasma concentra-

tions (<100 ng/ml) and have large volumesof distribution (>1 I/kg). In ruminant spe-cies, lipophilic bases passively diffuse

from the systemic circulation into ruminalfluid (pH 5.5-6.5), where they becometrapped by ionization. This is a feature oftheir usual pattern of distribution. The

magnitude of the volume of distribution ofa drug affects the half-life of the drug and

the fluctuation in steady-state concentra-tions on multiple dosing, but it does not in-fluence the average steady-state concen-tration. Volume of distribution is sensitiveto plasma protein binding and can there-fore be expected to vary in disease condi-tions where the protein binding is altered.

Volume of distribution is used in calcu-

lating the dose (mg/kg) required to pro-duce a plasma drug concentration withinthe therapeutic range: doseiv = Cp(ther) xVd(area)-

Administration of the drug by other thanthe intravenous route may require upwardadjustment of the dose level to compen-sate for incomplete systemic availability.

Half life

The half-life of a drug expresses the timerequired for the plasma concentration, aswell as the amount in the body, to de-

crease by 50% through the process ofelimination. For most drugs, the half-life isindependent of the dose administered,since at therapeutic dosage overall elimi-nation obeys first-order kinetics. The half-life of a small number of drugs is dose-

dependent, that is, elimination is zero-

order, in certain species. This can general-ly be attributed to saturation of a majorpathway of metabolism.

The half-lives of drugs that undergo ex-tensive hepatic metabolism vary widelyamong domestic animal species. The her-bivorous species (horses and ruminant ani-mals) generally metabolize lipid-solubledrugs more rapidly than the carnivorousspecies (dogs and cats). However, thereare notable exceptions to this trend, suchas theophylline in horses (Errecalde et al,1984; Ingvast-Larsson et al, 1985) andphenylbutazone (weak organic acid) in cat-tle (De Backer et al, 1980; Eberhardson et

al, 1979; Martin et al, 1984). These excep-tions defy explanation at the present time.

Most drugs that are eliminated mainlyby hepatic metabolism have shorter half-lives in horses than in dogs, while the half-life in humans may be considerably longer(table II).

It has been shown in a variety of mam-malian species that hepatic blood flow is

approximately equal to 1.5 I/min/kg liver

weight. With the notable exception of thehuman, antipyrine intrinsic clearance wasalso directly proportional to liver weight(Boxenbaum, 1980). Plasma antipyrinehalf-life is a useful index of the rate of he-

patic metabolism (microsomal oxidation) ofa variety of drugs, but it does not reflect

the activity of all hepatic microsomal meta-bolic pathways (Vesell et al, 1973).

Species variations in the half-life of

drugs that are eliminated by renal excre-tion (penicillins, cephalosporins and amino-glycoside antibiotics) are not of clinical sig-nificance. Their half-lives are generallylonger and clearances lower in horses thanin dogs, while volumes of distribution aresimilar in both species (table 111). This ob-servation can be related to the species dif-ference in efficiency of renal excretionmechanisms (Baggot, 1977).

For drugs that are eliminated by renalexcretion (unchanged in the urine), allo-

metric scaling of data obtained in animalscan be used to predict values of the phar-macokinetic parameters for these drugs inhumans (Mordenti, 1985).

The physiological basis of species vari-ations in the half-life of drugs that are elim-inated by a combination of biotransforma-tion and excretion processes could be

ascribed to differences in the rates ofmetabolic pathways and the influence ofurinary pH on the extent of renal tubularreabsorption of unchanged (parent) drug.The excretion of acidic drugs with pKa val-

ues within the range of urinary pH (5-8),such as phenobarbital and sulphona-mides, is enhanced in alkaline urine (hors-es) and decreased in acidic urine (dogs).The converse applies to organic bases (tri-methoprim and metronidazole). Urinary pHwill affect the excretion rate of a drug onlywhen tubular reabsorption occurs and afraction of the dose is excreted unchangedin the urine.

Half-life, in conjunction with the range oftherapeutic plasma concentrations, is usedto select the dosing interval for drugs thatshow a relationship between half-life andthe duration of the pharmacological effect.The half-life provides a good indication ofthe time required to reach a desired

steady-state concentration when the drugis administered by continuous intravenousinfusion. After infusing for a period corre-sponding to 4 times the half-life of the

drug, the plasma concentration will be

within 90% of the eventual steady-stateconcentration.

When selective avid binding of a drug totissues occurs, which is unrelated to the

principal pharmacological effect of the

drug, half-life may not reflect the gradualremoval of the bound drug. This is particu-larly so when the amount bound repre-sents only a small fraction of the dose ad-ministered. Although this situation may notbe of clinical significance, it represents aserious shortcoming in the use of half-lifeto predict withdrawal time for a drug in

food-producing species.

Systemic availability

The formulation of a drug product androute of administration determine the sys-temic availability of the drug, while the rateof absorption may influence the duration ofthe pharmacological effect.

The usual technique for estimating sys-temic availability of a drug uses the meth-od of corresponding areas. This entails

comparison of the total area under the

plasma concentration-time curve after

non-vascular (po, im, sc) administrationwith that after intravenous injection of thedrug (using appropriate dosage forms) in

the same animals: F = (!UCA4L/C!). Thistechnique for estimating systemic availabil-ity (sometimes called bioavailability) isbased on the assumption that clearance ofthe drug is not changed by the route of ad-ministration.

The systemic availability of a drug ad-ministered orally may be less than 100%,either because the drug is incompletely ab-sorbed or is metabolized in the gastrointes-tinal tract (lumen or mucosa) or by the liverbefore reaching the systemic circulation

(’first-pass’ effect). For drugs with high he-patic clearances (such as propranolol, lido-caine and morphine), it can be predictedthat the ’first-pass’ effect would substantial-ly decrease their systemic availability afteroral administration. Because of species dif-ferences in digestive physiology and in thecapacity of the liver to metabolize lipid-soluble drugs, wide species variations in

the extent of the ’first pass’ effect on drugproducts administered orally can be ex-pected to occur.

Incomplete systemic availability of drugsfrom parenteral dosage forms adminis-tered intramuscularly can be attributed ei-ther to precipitation of drug at the injectionsite or tissue irritation induced by constitu-ents of the formulation. The formulation of

each parenteral preparation must be con-sidered in specifying the withdrawal timefor a drug. Location of the injection site cancause variations in systemic availabilityand rate of absorption of drugs adminis-tered as aqueous suspensions or othersustained release preparations. By affect-ing the plasma concentrations attained,these variations in absorption can signifi-cantly influence the pharmacological ef-

fects produced or the effectiveness of anti-microbial therapy.

CHANGES IN DRUG DISPOSITION

Disposition is the term used to describe

the simultaneous effects of distribution and

elimination, that is, the processes that oc-cur subsequent to absorption of the drug.Even though therapeutic agents are usedpredominantly in diseased patients, thereare relatively few studies of the influenceof disease conditions on drug dispositionand dosage.

The disposition kinetics of a drug can beinfluenced by the capacity of the drug topenetrate cellular barriers (determined bypKa and lipid solubility), by the extent ofbinding to plasma proteins (mainly albu-min) and extravascular tissue constituents,by activity of drug-metabolizing enzymes(which determines rates of major pathwaysof metabolism), and by efficiency of excre-tion (mainly renal) mechanisms. Certain

physiological states (pregnancy, the neo-natal period), prolonged fasting (48 h orlonger), some disease conditions (fever,dehydration, chronic liver disease, renal

impairment), and certain types of drug in-teraction (plasma protein binding displace-ment, inhibition of drug metabolic path-ways or competition for carrier-mediatedexcretion processes) may alter the disposi-tion of drugs.

Attempts to correlate changes in dispo-sition (especially hepatic clearance) of

drugs that undergo extensive metabolismwith various liver function tests have been

generally unsuccessful. In chronic liver dis-ease, serum albumin concentration mightserve as a prognostic indicator of hepaticdrug-metabolizing activity. The clearancesof indocyanine green and antipyrine pro-vide quantitative assessment of different

aspects of liver function (Branch et al,1976). Indocyanine green (which is excret-ed unchanged in bile) can be used as amarker substance to indicate carrier-mediated hepatic uptake (hepatobiliarytransport) and liver blood flow, while anti-pyrine measures hepatic microsomal oxi-

dative activity. Since antipyrine has a lowhepatic extraction ratio, it is not a usefulmarker substance for metabolism (intrinsichepatic clearance) of drugs with clearanc-es that are highly dependent upon liver

blood flow (such as isoproterenol, lido-

caine, morphine).Unlike the poorly quantifiable situation

associated with liver disease, endogenouscreatinine clearance can be used to esti-

mate decreases in renal function (glomeru-lar filtration). Calculation of altered renal

clearance of a drug is based on the frac-

tion of normal renal function that is presentin the patient and requires knowledge ofthe fraction of dose usually excreted un-changed in the urine. The altered clear-

ance can be used to make adjustments inthe dosing rate.

Although infectious diseases have in

common the presence of fever, the chang-es that occur in drug disposition will varywith the pathophysiology of the disease

condition. Alteration in the volume of distri-

bution with concomitant change in plasmadrug concentrations appears to occur mostoften, while the half-life may or may not beaffected. These variations in altered phar-macokinetic behavior lead to uncertainty in

predicting dosage adjustments that maybe required. The use of combined drugtherapy, particularly when the possibility ofdrug interaction exists, would further com-plicate understanding the altered pharma-cokinetic-pharmacodynamic relationship.

INTERPRETATION OF ALTEREDDISPOSITION

The ability to interpret alterations in drugdisposition requires an understanding ofthe interrelationship among the various

pharmacokinetic parameters and the basisof their calculation.

The time course of drug in the body de-pends upon both the volume of distributionand systemic clearance, while half-life re-flects the relationship between these twoparameters:

Altered disposition can be due to changesin either or both of the basic parameters,volume of distribution and clearance; thushalf-life (which is a derived pharmacokinet-ic term) will not necessarily reflect an antic-ipated change in drug elimination (tableIV). Interspecies comparisons of drug me-tabolism rates should use intrinsic clear-

ance as the pharmacokinetic parameter ofchoice.

The volume of distribution at steadystate, unlike Vd(.rea) is independent of

changes in the rate constant for drug elimi-nation. As the elimination rate constant de-

creases, Vd!area) approaches Vd{ss)’ Thevolume of distribution at steady state rep-resents the volume in which a drug wouldappear to be distributed during steadystate if the drug existed throughout thatvolume at the same concentration as in the

plasma. This term is the proportionalityconstant between the amount of drug inthe body and the plasma concentration atsteady state. It can be calculated by theuse of areas (Benet and Galeazzi, 1979):

where AUMC is the area under the firstmoment of the plasma concentration-timecurve, that is, the area under the curve ofthe product of time and plasma concentra-tion over the time span zero to infinity. Thesignificance of AUMC lies in the fact thatthe fraction AUMClAUC is equal to the av-erage time a drug resides in the body. Thisvalue is generally called the mean resi-dence time (MRT), which is the time when63.2% (1.44 x half-life) of an intravenousdose has been eliminated.

Fever induced by E coli endotoxin pro-duced changes in pharmacokinetic param-eters similar to those seen in IBR virus in-fection (Abdullah and Baggot, 1986). Ineach disease condition, statistically signifi-cant corresponding changes occurred inthe steady-state volume of distribution andsystemic clearance of the drug, while thehalf-life remained unchanged. It followsthat half-life alone is not a reliable indicatorof changes in drug disposition induced bydisease conditions.

Change in drug binding to plasma pro-teins or extravascular tissue constituentsor in the relative volume of body fluid com-partments could alter the volume of distri-bution. By affecting the drug concentra-tions in the plasma and more importantlyat the site of action, the altered volume ofdistribution could change the dose-effectrelationship.

Alterations in the clearance of drugsthat are eliminated mainly by renal excre-tion unchanged in the urine can be esti-mated from the decrease in renal function

(based on endogenous creatinine clear-

ance).Although various types of liver disease

can alter the disposition (clearance and/orvolume of distribution) of a number of

drugs (antipyrine, lidocaine, propranolol,diazepam) or increase the concentration offree (unbound) drug in the plasma (due tohypoalbuminemia), it is not possible to pre-dict the changes that will occur in pharma-cokinetic behavior of a drug or how theymay affect the dose-effect relationship.The detailed study of the disposition of cer-tain indicator (test) substances in the vari-ous types and stages of liver disease ap-pears to offer the most promisingapproach.

Changes in pharmacodynamic activitythat are related only indirectly to pharma-

cokinetic behavior may occur in some dis-ease conditions. An increased sensitivity tothe pharmacological effects of certain

drugs may occur and could be the result offunctional or morphological modification ofthe drug receptors, or interaction with sub-stances retained in animals with renal dys-function. The anesthesia-inducing dose ofthiopental, for example, is substantiallylower in uremic animals. This could be

partly attributed to decreased protein bind-ing.

COMBINED PHARMACOKINETIC-PHARMACODYNAMIC MODELING

Several compartmental and non-

compartmental approaches have been

successfully applied to the combined phar-macokinetic-pharmacodynamic modelingof various drugs (Colburn, 1981; 1987).For many drug classes the pharmacologi-cal effects produced correlate well with theplasma drug concentrations. This situationapplies when the effects are direct and im-mediate, which infers that the concentra-tions at the site of action and in the plasmaare essentially in equilibrium. When phar-macological effects are not directly relatedto plasma drug concentrations, the com-plexity of the relationship is determined bythe extent of separation between the ob-served effect and the plasma concentra-tions measured. Dissociation can be attrib-uted to the drug exerting an indirect effect,to redistribution or delayed access to thesite of action, or be due to the character ofthe drug-receptor interaction. It is onlythrough the further development and eval-uation of combined pharmacokinetic-pharmacodynamic modeling techniquesthat such complex dose-effect relation-

ships can be elucidated.

REFERENCES

Abdullah AS, Baggot JD (1986) Influence of in-duced disease states on the disposition ki-netics of imidocarb in goats. J Vet Pharma-col Ther 9, 192-197

Baggot JD (1977) Principles of Drug Dispositionin Domestic Animals: The Basis of Veteri-

nary Clinical Pharmacology. Saunders, Phila-delphia

Benet LZ, Galeazzi RL (1979) Noncompartmen-tal determination of the steady state volumeof distribution. J Pharm Sci 68, 1071-1074

Boxenbaum H (1980) Interspecies variation in

liver weight, hepatic blood flow, and antipy-rine intrinsic clearance: extrapolation of datato benzodiazepines and phenytoin. J Phar-macokinet Biopharm 2, 165-176 6

Branch RA, James JA, Read AE (1976) Theclearance of antipyrine and indocyaninegreen in normal subjects and in patients withchronic liver disease. Clin Pharmacol Ther

20, 81-89

Colburn WA (1981) Simultaneous pharmacoki-netic/pharmacodynamic modeling. J Pharma-cokinet Biopharm 9, 367-388

Colburn WA (1987) Pharmacokinetic/pharmaco-dynamic modeling: what it is. J Pharmacoki-net Biopharm 15, 545-553

De Backer P, Braeckman R, Belpaire F, De-backere M (1980) Bioavailability and phar-macokinetics of phenylbutazone in the cow.J Vet Pharmacol Ther 3, 29-33

Eberhardson B, Olsson G, Appelgren LE, Ja-cobsson SO (1979) Pharmacokinetic studiesof phenylbutazone in cattle. J Vet PharmacolTher2, 31-37

Errecalde JO, Button C, Baggot JD, MuldersMSG (1984) Pharmacokinetics and bioavaila-bility of theophylline in horses. J Vet Pharma-col Ther7, 255-263

Ingvast-Larsson C, Paalzow G, Paalzow L, Ot-tosson T, Lindholm A, Appelgren LE (1985)Pharmacokinetic studies of theophylline inhorses. J Vet Pharmacol Ther 8, 76-81

Martin K, Andersson L, Stridsberg M, Wiese B,Appelgren LE (1984) Plasma concentration,mammary excretion and side-effects of phe-nylbutazone after repeated oral administra-tion in healthy cows. J Vet Pharmacol Ther7,131-138

Mordenti J (1985) Pharmacokinetic scale-up: ac-curate prediction of human pharmacokineticprofiles from animal data. J Pharm Sci 74,1097-1099

Schwinghammer TL, Kroboth PD (1988) Basicconcepts in pharmacodynamic modeling. JClin Pharmacol 28, 388-394

van Miert ASJPAM (1989) Extrapolation of phar-macological and toxicological data based onmetabolic weight. Arch Exp Vet Med 43, 481-488

Vesell ES, Lee CJ, Passananti GT, Shively CA(1973) Relationship between plasma antipy-rine half-lives and hepatic microsomal drugmetabolism in dogs. Pharmacology 10, 317-328