Chapter 2
`
`Guidelines for Collection and Analysis of ftiarmacokinetic Data
`
`of these guidelines and relationships. This material may
`be helful as a checklist in designing animal or human
`experiments itt phannatokineties and in reviewing drug
`disposition reports; with greater elaboration: it has served
`os a basis for a graduate course in physiologic pharmaco-
`.kinetiCS.
`
`CONTEXT OF PHARIVIACOKINETICS
`
`-iit'
`
`A pharmacokinetic analysis must be made in Conte 'V of, be
`consistent' with. and explain the array of basic data regard-
`ing the properties and disposition characteristics of the
`Lug
`-The tasks of model and equation selection and inter-
`prctation of date require a fundamental >appreciation and
`iniegration of principles of physiology, pharmacology.
`biochernistry, physiochemical, analytical methodology,
`r -ithematics, and statistichannacokinetics has derived
`from these disciplines, and the relevant aspects of many of
`these areas must be considered in reaching any conclusions
`regarding a particular set of d3ta7. The physicochemical
`properties of a drug such as chemi -al form (salt, ester, com-
`plex). stability, partition coefficient, pNa, and molecular
`voight can affect drug aborption, distribution, and clear-
`ance. A drug disposition profile must be correlated with
`studies of structure-activity, disposition in alternative spe-
`cies: perfused organ experiments, tissue or mieresomal me-
`tabolism, tissue drug residues, disease-state effects, and
`pharmacology Incl toxicology, For example, a much larger
`I-D-J ftir oral doses of a drug compared with parenteral
`administration may be indicative of eithet poor gastrointes-
`final absorption (low aqueous solubility) or a substantial
`first-pass eiTect. Drug metabolism pathways may differ
`among spi?cies, but the biotransformatinn rate CV. and
`K,) of microsoines, homogenates, and perfused organs cait
`riften be applied directly to whole body disposition rates
`and often correlate among species.1'
`In general, the pharmaeokinetic inodel and analysis
`should either conform to,
`.q- accouru for, the known
`viper:its and accumutated data related to the drug. One
`sm of disposition data may misrepresent the characteris,
`tics of the dnig because of any one or a combination of
`reasons. Experienced judgrriei it is usually required in the
`final interpretation of any experimental findings and anal-
`ysis.
`
`ARRAY OF BASIC DATA
`
`Phannaccikinetic studies often serve to answer specific
`questions about the properties of
`drug. For example, a
`limited experimental protocol can easily resolve the ques-
`tion of how renal im.pairment affects the systemic clearance
`of anantihiotic. in the total design and implementation of
`
`pharouicokinetie studie.s, n ideal mid complete array of
`experimental data should include several eonsiderations9
`A. The doswge form should e pre-anal-A. All caleula,
`nons stem froM krIX)V,j4:
`of the exact dose given
`(L.
`- Dose / AIX laiea under the plasma concentration-time
`curve1)-Mt sr commercial dosage forms are inexact, and
`content uniformity should be examined. Vials or ampules
`of injectables typically contain some overage and require
`analysis or aliquoting for administration of a precise dose.
`Solid dosage forms are required w yield an average of the
`stated quantity of drug with limited variability. but both
`injectable and solid for nIS may be inaccurate for phannaco-
`kinetic purposes.
`purposes. Manninen and Korilonen4 provide an ex-
`cellent example of both the variability and lack of stated
`quantity of digoxin in many commercial tablets. One prod-
`uct contained a range of :19 to /39% of the stated D.25-
`mg dose of digc.).xl.n. whereas the most uniform product,
`La.noxin, exhibited a range of about 95 to 106% for one
`batch of drug. To evaluate the potential uncertainty of the
`dose of drug used in dispoiii don studies, it may be necessary
`to collect and analyze replicate doses of the product used.
`Poorly soluble and highly potent drugs are of most concern
`regarding erratic formulation.
`B. Act:wag in administration ofthe doseshould be con-
`firmed. All doses should he timed 1,-,,taerly for starting time
`and duration of administrations. For ease in subsequent
`calculations, pharmacokinetic equations can he used to
`correct data from short-n-3ln inhision studies to the inter-
`cepts expected after bolus injection. The. particular materi-
`als used in drug administration may cause loss of drug. In
`one Of the most dramatic example5. MacKichan
`al.'
`to
`Immediate loss of about SO4 of a dose of intravenous
`diazepam by adsorption during passage through the plastic
`tubing of an infusion set. toline flOration can also Nignifi.-
`candy reduce the potency of drugs administered intta.ve.-
`neusly.'
`C. Attention to fueritocLi wra" sites optlood collection is
`needed. Ideally, blood samples. should he collected by direct
`venipunotute in clean glass tubes without anticoagulant.
`Otherwise. the presence of possible artifacts should he
`tested. In the absence of any in vitro artifacts, sonoro and
`plasma concentrations are 'usually identical, and these
`terms are commonly used interchangeably. However, Mere
`are several reasons why they may not be identical. For ex-
`ample, the presence of heparin can result in increased tree
`fatty acid conceotration
`causing altered pldstna protein
`binding! Also, the type of blood collection tube or antico-
`agulant may he a factor.' If protein binding is temperature
`dependent, it may be necessary to centrifuge the blood
`sample at 3rC to avoid changes in red blood cell-plasma
`distribution of some compounds." These problems primar-
`ily pertain to weak bases, fa,ich as propranoloi and imipra-
`mine for which binding to ol acid glyunprotein is apprecia-
`ble and displacement alters plasma-red blood cell drug
`distribution.
`
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`io
`
`Basic CormaRts arid Priptes
`
`Plasma or i?:,r1.1rn protein binding and red blood cell par-
`tning should be measured at Trt: river the eKpecred
`range of plasma drug concentrations. Both rate and degree
`of binding and uptake ace theowtically important. This hi-
`ft.mitatioo rtia be especially needed for intelpretation or
`normalization (..4 nonlinear dosition patwrns, Some-
`of blood (7ollection and the presence or a
`times the
`toutiqui can alter the composition of the blood sample:
`M:1-tirct proteins. calcium. and magileSidril CiMONIttatiOri,`,
`during \.enou stasis,.
`ri5;e by 5 to
`One of the h;ljot assimptions use4 in most pharmaco-
`kinetic suds is that venous blood colle(Jed from one
`site adequately reflects circulating arterial blood concen-
`trations., For practical purposes, venous Hood samples
`are wally collected. The phartnacoMnetic analysis Mai"
`lwed io be ',awhet qualified, hi.. causc. etrterial and capil-
`lury blond cora.:entratiotts may differ markedly from ve-
`nous blood concentrations of many drugs. '1 The AU( Of
`arTerial versus venous blood is expected to be idelltirai
`for a nonclearlog organ, and [bus the principal difference
`expected is in distribution volumes. Physiologically, ()Tao
`uptake of drugs occurs froto the arterial blood, t':inci dear
`ance organ models are based on arterial-venous extraction
`principles.
`Serum for blood; COnCentra ion data after ;nrrave-
`nulls njed ion (bolas Or infusion) provides pattieli Cha
`iza tion qf drug disposition properaps. Accurate ases.stnent
`of volumes of distribution, distribution clearance
`and systemic clearance ÍCI..) can best be attained with in tra-
`VeROICS Virashow data_
`E. serum (or Hood) concentratiOn clam after wal
`oíihr dnig in sohrlion and common dosage forms provides
`additional phartm-1,-.1tictie pararpretors releiteei To ahsorp-
`tion and inZrinsie c-learriwo. The fioses ior rewitant serum
`t ornpztrabk
`or blood concentraTions of drug:: should
`those' from the intravenotB dtne. Thee data permit
`or hios.s.-aifahf
`as?,4essment nf either oral clearance
`. if Fete-
`(r1. and of the mean ahmtption mirk
`Vailt, other routes of administration should he studied,
`For these, he U.S. Food ilfid Drug Adruinistration &DA)
`ibould be con-
`tt di
`for bioavailability
`guidelines
`suited.' 2
`::I.oth oral and inrrapcnous;
`F. !htt-v dosiipy
`should be administered ro span the usual therapeutic range
`of the drug to permit ar6essinent of rimsible flose-depen-
`&nee r,nonlinearity) in absorption, distribution, zkod iiní
`oa ion.
`fii.nction o riFilft,
`Uritiarvexcri.4.tion rates qtri
`doie, Ond rolre qraCIMil'istration) shott id tie FiZeaSti red to
`Urinary excretion is often a
`cick:Ornpatly the obow
`major route of drug elimination, and analyses permit quan-
`titation of renal eleatance (C.1..1;3. Collection of other excreta
`or body fluids (feces, bile, milk, saliva', may perrnit determi-
`mation of other relevant elimination or (Hsu/Ann:Iona/ path-
`ways.
`
`A-iany drug metabolites are either pharmacologically
`active or othow;:,' of phattnarokinetic interest. Phase
`producis such as hydroxylated or dernethylated metabo-
`lites are most corranordy either active or toxic.1' Their mea-
`surement will allow evaluation 01 AUG and mean residence
`time 1,1 IM and perhaps permit quantitation DI:metabolite
`formation and dispmition clearances.
`experinle3t.s are
`silty if rho-al:N.1W( .11517 Of the drug relies on rhroair dosing
`or steady-state concentratiom, flfl dutation of multiple-
`dosing in relation to the terminal half-life is crucial for as-
`certaining appLcability to steady-state conditions, Com-
`parative single-dose and multiple-dose studie:s permit fur
`tiler assessment of linearity or allow determination of
`chronic or time-dependent. drug effects (nonstationarity),
`such as enzyme induction," unusual accumulation,' or
`drug-induced alterations in disposition. For example anti-
`noglycoside uptake into tissues k extremely slow and diffi-
`cult to assess from single-dose studies. Multiple-dose wash-
`ig 2-11 lcd to observation of a slow
`out measureruvru
`disposition phase for gentaraicin that was the result of tis-
`sue accumulation and release."
`J. TISSIW analyses add reality and specificity t4i drug dis-
`tribution (,lairactcti6fiCS. COMpwhensive studies in animals
`permit detection of unusual tissue aftinitieS Whitt generat-
`ing partition coefficients IK,.) for individual tissues CV,,.).
`This can lead to complete phygiologic models for the drug
`in each species studied. Autopsy or biopsy studies in man
`may eXARrid or conipIentent phatmacokinetic expecations:
`This approach was found to be extremely helpful in con-
`firming the strong (issue binding ofgentamicin in man that
`was anticipated on the basis of serum concentration pro.
`tiles (.4.!e inset rit Fig,
`K. Sultabh' drug ?lisposition sludiP-S in patients with
`various 4i;wases and agcs or giuvn secondary drugs Jrm
`Ow basis of clinical pharmacokinetics. Perturbations in
`organ function, blood flom., or response will often alter
`drug disposition in a way that may warrant goantitative
`chameterization. General principles may not always apply,
`and each drug needs individtrali'7,ed study. For example,
`although hepatic dysfunction may dirninizat the rate of
`oxidation of many drugs, sorne compounds, such as oxa-
`zepant and lorazeparn, are predominantly metabolized by
`giticoronide conjugation, a process largefy unaffected by
`liver diseases such as cirrhosis.' Each discase state may
`require evaluation of direct effects on pharrnacokineric
`prot7esses such as changes iu renal clearance .ilused by
`kidney disease. However, indirect changes also require
`attention, such as the effects cm both distribution and
`clearance caused by altered plasma protein binding.'
`Commonly enounrered patient metres such as 1,4noking
`habit° and obesity may cause unusual changes in drug
`disposition and require specific study and notation in
`patient survey.
`
`j
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`

`

`Chapter 2 it Guidelines for Collection and Analysis a Pharrnacokinetic Data
`
`Dose
`
`etaritml
`
`---........
`
`\=, Uptake i
`I ---)" ti 'T issue
`....
`.1.....
`i
`, rI Reiease
`Penai dearance
`
`I,
`
`5.0 ---
`
`A
`
`E
`
`cit
`
`C
`;0;
`
`to
`
`E
`
`1.
`
`0 4 .t,
`
`1
`0 2 i---
`
`0.1
`
`D
`
`Fite 2-1 Plasma cenctintr--
`tion-time profile for gervtatnion
`dispolittion during multiple-dos-
`ing in patient showino the pro-
`longed terminal phase CVUSeCi
`by strong
`binding. These
`ìr characterized with a
`(lido
`two-f.ompartment model finseri
`that included prediction of drug
`rernairiing in the body or, au-
`t)psy of sorne patients tinset.
`Dato from Schentag et
`
`Amount. mg
`
`300
`
`2 200
`
`;
`/001-
`
`)164
`
`o
`
`200
`106.
`Measured
`
`S00
`
`2
`
`4
`
`a
`
`-
`
`10
`
`80 m9
`Pestr.
`
`12
`
`4
`
`Time, days
`
`16
`
`18
`
`20
`
`22
`
`L Akitty efitotiolo of drug disposition can be resolved
`from .eleetrii, carefully designoi studies, and alternatin,
`types of ilkiromultiwF niqV
`StíffitielIC tn lq-didate
`ssumptions and reduce experifacrtral. proa4tire,,.. The in -
`vestigator!,, obligation is to adequately assess the litera-
`ture, to avoid Ilitwarrat'iteci assumptions, and to seek ex,
`perimental strategies that would resolve a proposed
`itypotlivz;is.
`A comprehensive overview of phatInacokinijic need.
`drug citc'celopment has been csonstructed by Balarn e;
`
`yield total drug and metabolite activity and possibly the
`products of radiolysis, Separation of parent drug and indi-
`vidual metabolites is required for specificity. Microbiologie.
`enzymatic, and immunniissays are ()hen of uncertain speci-
`ficity, and matris effects rimy require preparation of stan-
`dards in each patienr:, pretreatment pknr.r1;4, NIOSt drug
`companies provi& analytical grade ,,;arnplc's of their drugs
`land soinetimei tatlabolites) o qbaliried investigators on
`Written request.
`
`DRUG ASSAYS
`
`Certaintr Of specificity. seminivity. and accuracy in Mea-
`rif drugs Ond their
`k i'i Sine qua n0n
`in pharrnocokinetics and
`consideriThic lttentiort.
`Guideline; for quality aSStit,:inCf! in laboratory anniv,t.,,z
`have been concisely SUMinarrzed by the American Chemi-
`ca ,>r
`- ' it is rirm.T con imi.mpla( e to report rhe inca ritY,
`mid high drug
`...:iiefriCieTn.
`f.31 the
`ciificentrations, the minimum if.:'%:t4 of detection. and the
`prm-xdure; used to assure Tecificity and slabiiiry, epe-
`rJi-: in ;tie prezimce of intqabolites secondary drugs, and
`in specimens from diseased patients. Microhiologic assays
`are notoriously unreliable with problems caused by other
`nti ori cs and actil,T atel.
`tes
`An extreme case cif metabolite inclusion is in use of ra-
`dioisotopic tracers: total radik)isotope counts .¡Ierierally
`
`Sample Handling
`Coupled viti as..:ay reliability is concern [or the stability of
`4.Inig in biologic specialf!ns, even in the f.riv.ert5.aate.
`UntOlai in that it is less stable when frozen than \Alen
`refrigerated,' SOflii . drug t:sters, such as hetacillin oc pro--
`drug of arnpicill in), continue hydrolyzing in binod and dur-
`ing the bioassay. Petticinz'Amitte k umtable in the pre!,4frice ut
`plasnin proleins,
`td
`n ediate deproteination aber blood
`co I iec ti On aoids lu of ri4duccd parnciIatninc betow naly-
`cyciosno,rine ibtst a
`t¡ed in EULA mther tharkhepa-
`rinized blood as the lirter yields red blood cell aggregates
`that inCfekifie assay variability,' Measurement of drug stabil.
`its,' in blood will reveal whett er h.ydrolysis can occur in blood
`or -whether exposure TO ntlur liody organs is required. Add i
`tional concerns in handling samples front a pharrnacold-
`ne tie stud y. include labeling and record-keeping procedures
`and documentation of .g.t.irage conditions.
`
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`

`

`12
`
`Basic Concepts and Principies
`
`Sample Timing
`.,\ppropriate pharinacoLine:tic evaluation requires properly
`timed specimens. The simplest and least ambiguous expel.-
`ient is the determination of systemic plartia clearance
`(luri g continuous infusion at qeady-,,,tate:
`
`(71f.
`
`f
`
`infusion rao:i ;and C,, is the steady-state
`'Where k
`plasma concentrati)n.. For this equation to apply, the infu-
`must be sufficiently long (about five terminal
`sion
`divosition balf-livesJ to t1lo steady-state to be attained:
`Alternatively. a loading dose or .ihtilt-terin infusion may he
`administered to more rapidly aillieve equilibrium?'
`Practical methods, are a vailable'''' for di-?signing optimal
`sampling strategieS tor kinetic expt.Tiol,.,-1.1!:,., in ,Thich the
`number of se.drnens is limited, such as in the clinic. Opti-
`mal dgn largely depcnd on the likely "true rnodel pa-
`rameter values, the structure of the model. and measure-
`met t error% A squenta.I approaCh has been iadvor:ziteci Wit h
`pilot studies and a sampling schedule that distribute5> time
`the hrs.
`points over the major phases of drug tiispnsitin
`step, Subsequeru experiments can then resolve a specirie
`hypothesis.
`common and severe problem in applied phartnacoki-
`ig the inadequate or incomplete measurement Of
`nCLIC.
`drug washout from the SysTern, either because of premature
`termination of sample collection of because of anal,rtical
`limitations. The -true terminal disposition phase [pest be
`QXattlitled for rnost aspeTts of data treatment and interpre-
`example, the early distributive
`tation to be accurate,
`phase of arninoglycosidf.-i disposition measured by bioassay
`had long been accepted as the only phase, yet more sensi-
`tive radiuirumuntiassdys, lengthier sample collection:
`walit revealed the sloer
`evaluation of
`phase of prolonged drug release from tissues iTig, 2-1).
`The two prim a ry physiologic parame,ters in pharrnacoki-
`netics, natnely .,ysternic ilearance and steady-siate volume
`of distribution, can be tA easily calculated by use of the
`arya 1.111dCr the plart141 CUOCentratjOil-tifilk-! CLIP,T ;,..5%.+J(7)
`il)C1 the area under the rnotner.A curve (A.UNK:). Both area
`valucs requiri: exuzpolation ot pla5rna ConE.:erlinatiom'i to
`time infinity, and the AUNIC.: is. in particular, prone to exag-
`gerated error from an inaccurate terminai slope.:'' If analyt-
`ical of etilic a! frOVoiltairOS Iftoir. bkh-H1 situple
`extended saliva or urine col!ection ismiy aid in defining the
`terminal dispoMtion sIena vhile adding (.ine or two ¡Aber
`pharmacokinetic parameters to tht:, analysis. Urine may be
`particularly useful in this regard it renal clearance is tin..
`ear), as sample volumes are large and urine concentrations
`often greatly exceed plasma value$.
`The"roidpoint" (C:: is generally the rthist dff,irable time
`to collect blood samples to match an excretion interval to
`time-dependent clearance process:'''
`:.isqss
`
`- AU('
`
`,47nown Etcrete4
`
`(Erl. 2..2)
`
`EVe7ti0,1 HOte
`
`'File arithmetic mean time is acceptable for slow processes,
`but errors will be incurred if the kinetic process produces
`rapid chinges in plasma concentrations; it is common to
`miss an early exponential phase of drug disposition be-
`cause of infrequent blood sampling. For a polyexponenrig
`the total Al IC is
`curve With intercepts Ci and :;lopes of
`
`TIC
`
`(Eq. 2-3)
`
`If the initial distributive phase missing tarea
`then the error incurred in calculation of a clearance param-
`eter (a -= Dose AU° k
`
`error
`
`1001C.
`.41R:
`
`?A)
`
`BASIC PHYSIOLOGIC PARAMETERS
`
`The evolution of complete physiologic models' and clear-
`ance concepts applied to perfused organ systems,'"-:''' with
`il-te restrictions incurred by the limited in vivo 'visibility of-
`oo disposition profiles,
`fered by most blood or plasma
`has led to The ust: of partial physiologk models for descrip-
`tion Of ph:a rmacokinetic data. One such model is shown in
`Figure 2-2. Its construction ;and use Amuld be viewed with
`some conceptual flexibility. and this material oll apply to
`linear processes unless stated otherwise.
`
`Volumes
`is :oT5ìd-
`l'he drug coneent.ratiori n blood or piasimi
`(:Ted to be part of the central compartment (V, 1. The mini-
`
`CL
`
`C.,
`
`Figure 2-2 Basic serniphysiologir,' pharmacokinetic model for
`lrug distribution and efimination (syrnbois are defined in the
`text), The clearanc,T organ is phormacoldnetically perceived as
`separate from other compartments for driigs with higb intrinsic'
`clearances (CL,,t), aliOVVinf.3 eliaracterization of the irsti-pas'i
`input,
`
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`

`Chapter 2 1 Guidelines for Collection and Analysis of Pharrnscokinetic Data
`
`13
`
`TABLE 2-1 IN PHYSIOLOGIC DETERMINANTS OF
`DRUG PARTITION OR DISTRIBUTION RATIOS
`BETWEEN TISSUES AND PLASMA
`
`Active transport
`Dorman ion effec.:t
`pH di'fierertcas
`
`Plasma protein binding
`Ts ula binding
`Lpd parto:;aning
`
`but, either becawe
`tnuni value (}f\) j
`drug diffuses rapidly out of plasma or th number of imrly
`time data are limited, the Ve value often exceeds V,.
`of course, preheat' in
`Drug., located oatf.,;ide
`tiSkte.S. The apparent volume of the t ¡SAW compartmont
`:VI) has two basic determinunts: physiologic ...vt,>:ight or
`LifU tJf poch
`(Vfl. :1 and partition. Or distribution faclor.,
`arialy5is of piZISIXIa. Cf.a wen.tration-drue profdes, 05-
`SLR'S tust commonly he clustered together (including the
`clearing organs), thirs
`
`rhis equation leads to the definition of one of he inimary
`phatmacokinetic paratnetes.., with a phy.;illiugic basi.--;, vol
`une of distribution at steady-suite A:.,):
`
`if plasura and tis?;tie binding are the sole delerrninatm of
`m)1uhornogeneous distfibution (.4 drug in the body, then
`\
`definttion
`fs
`
`iEq. 2-7;
`
`and f, tire the tractions ot unbound drug in
`vhere
`plasma and tisue..' Other factors may also contribute to
`the apparent portilion cEtefficient of drugs between tissues
`triri plasma asible
`Since, by definition,
`and
`constitute total body \yelp t rfl3W)
`
`then he quotient
`
`7.13I1,"
`
`;Di, 2.-9)
`
`defines she distribution coefficient ',I<D) a physicochemical
`and phyiologic measure of the average tissue to plasma
`ratio of the drug throughout the body. Approximate values
`of K, and che primary mtionalization of the size of Ko are
`provided in Table 2-: for several common drugs. Normal-
`intion of V for TBW i duds of value for generating the
`Kn and for snaking inser-individual and interspecies con."
`parsons of this parameter,
`One qualification of V.. is needed. Drug equilibration
`between
`L1t and iitiStle of a clearing organ is affected
`by blood flow (Q11) and intrinsic clearance tCL)
`For
`hepatic tisue tls :,.'ir.qds the following relation5hip be-
`tween the trot partition coefficient Ki and the lower,
`apparent value RA' that would be experimentally mea-
`sured ru SiCady-:,lat,
`
`,
`
`tL
`Q:,
`
`. "1:,10)
`
`Distribution Clearance
`lewa apprzsci at NI eir,nent of the basic ph a trnacokin etic
`nropenit., of drugs is ti:t distribution clearance f(.;l., nïr
`isne;.cornpartinents.il clearances This terra reflects the fl()%v
`
`TABLE 2-2
`DISTRIBUTION COEFFICIENTS ¡kr,) FOR VARIOUS DRUGS AND PlIOSABLE PHYSIOLOGIC
`(PHYSICOCHEMICAL) CAUSE
`
`DRUG
`
`inciocvarline greer:
`lnulm
`
`Antipyrine
`41'intarniein
`Tetracycline
`Diazepam
`Digoxin
`Istpraertine
`
`V
`TBVII
`
`CUR'S
`0.2G
`
`0.6
`
`1.1
`7.6
`1.7
`8.0
`10.0
`
`EXPLANATIONINDICATION
`
`Strong binding to plasmo protein:3 and limited extraval.n.ilar perrneabflty
`cur v'ï9ht
`pmie and intettitiai fluid owin!_j io rlrge
`Distribution iimitcd
`(,W0) ant; lipid insolobOltv
`Moderate plasma binding ond distribution prirnariy into total body water
`Slight plasma blnding and fairly uniform d,stribution into total body water
`Strong tissue nindino (common to enlincglycosdes)
`Strong tissue binding to c,alcium in bone
`Appreciable lipid prtitioning
`Strong binding to NaiKtranspon ATFaso n cell membranes
`Strong tissue binding ;common to weak be...,es-1
`
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`

`

`V may) Kr.
`
`Distance
`
`Figure 2-4 The "vveli-stirred s' or "jar" model (left) for hepatic
`uptake and metabolism (V,k.) of drug in which in,,,,nntaheous
`venous and hepatic equilibration of unbound (C) drug is as-
`sumed, Inflow and outflow (Q) are assumed to be identical. The
`''tube" or "parallel tube model (right) for hepatic uptake and
`metabolism of drug in which venous concentrations (CO decline
`monoexpon.entially as flow (0) carries drug past homogeneousiy
`distributed sites of biotransforrnation. The log-rnean concentra-
`Von (C) in the tube is indicated.
`
`(V., K) or renal filtration (GFR) and transport íTTh. ir)
`on removal of drug from the body and allows for some
`effects of route of administration (e.g., first-pass).
`il\-tio types of clearing organ models are commonly used
`for hepatic elimination: the "jar" or venous equilibrium
`model' and the "tube" model
`dig. 2-4). Both include
`blood flow for drug access to the organ and, as shown in
`the figure, assume that free or unbound drug (f) in plasma
`equilibrates with free drug in he tissue available to en-
`ZyineS. The jar model assumes that drug in arterial blood
`tC,,) entering the clearing organ instantane.nusly equili-
`brates with that in the venous blood ((:-,..). The tube model
`ast:Annes that a drug concentration gradient exists down the
`tube, with enzyme:,; acting on declining perfusate concen-
`trations.
`The jar model yields the following relationship for he-
`patic cii,rarance:
`
`Q
`(.2,
`
`Cf,te
`
`Y C7 it
`
`x E
`
`lEq. 2-12)
`
`where intrinsic clearance is the ratio of V. I 1.;', for linear
`blotransformation and EH. is the extraction ratio.
`The corresponding equation for (11. described by the
`tube model is
`
`(EC1, 2-13)
`
`Figure 2-5 depicts the dual effects of blond flow and intrin-
`sic clearance on hepatic clearance for the two clearance
`
`14
`
`Basic' Concepts and Principles
`
`orpermeabi lity property o f d rugs; between pktsrn a o nci tis-
`sue spaces.
`Renkin characterized distribution. clearance in terms of
`transeapillary moverrn-mt of small molecular weight sub-
`stances.' The model proposed is depicted in Figure 2-3.
`Drug transfer from 'blood to tissues is represented by flow
`down a cylindrical tube (Q) Ivial permeability (P) deter-
`mined by diffusion across the capillaries. Distribution
`clearance is thus defined by flow and permeability itt:C0111-
`ing to the following relationship:
`
`CL,,
`
`11
`
`e 'Px"
`
`CE. 2-11)
`
`Compounds with high tissue permeability will exhibit a lim-
`iting CJ D of( while those with low permeability are limited
`by V These concepts have been applied by Stec and Atkin-
`son' to a multicompartment .model of procainamide and
`NAPA disposition and used to predict. the extent of hemody-
`namic changes caused by heroodialysis. The flow or perme-
`ability coefficient can be calculated for drugs exhibiting po-
`lyexponential disposition and is of more fundamental value
`than intercompartmental rate constants,
`
`Hepatic Clearance
`The model shown in Figure 2-3 represents the coMMOn
`SitUatiOn in which drug must pass through a specific organ
`such as the liver or kidney for elimination. It does not apply
`to enzymatic hydrolysis in blood. This type of model reflects
`the dual role of blood flow (C,?) and either bio transformation
`
`e
`
`Distance
`
`C,
`
`C
`
`ooo
`
`Figure 2-3 Model for distribution clearance (et.t,) in which blood
`flow (0) along the cylindrical tube and capillary permeabilitl, (P)
`are the primary determinants of drug loss from arterial blood
`Drug concentrations in the tube will decline monoexponen-
`flatly according to ffistance (length) along the tube, emeraing at
`the various concentration (CV).
`
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`

`Chapter 2 RI Guidelines for Collection and Analysis 0 Phermacokinetic Data
`
`15
`
`lobe riloclet
`
`o
`
`20
`
`0
`
`u 0
`C.71,.
`
`))) 0
`
`-e o
`
`Figure 2-5 Re.lation!--ihips i-imong hepatic iiirance (Ct,), intrin,
`sic Cjeeran Ce (GL,), and he.i.:tic biood flow (0,4d for the ¡ar fieft)
`and tubo (nghti models. Tho eqoations are shown wthout the
`orol'oin-i)indinu facto, (sea Eqs. 2-12 and 2-13i.
`
`-
`
`orp,an models, P:otil to6dels prd:t
`.lirh f
`ikyer ( ...
`ior Ci.
`prutcin hindiug
`Ct",,:' 0.135CIICC
`cnrisidorationy and an upper Va hie
`of
`Qu. Thus, Cl.
`cicarance drugs
`t'SSettliall,,,. equal In thf,: produCt
`intrinsid olt;arane tnd he fraction urihuund in plipwna,
`hepetic ctaxin;& ïU be organ blood now.
`Tht,
`if' the uace thi? rwo models divergo
`,.,o en by the
`:',oinehat in chaa(ltNizitig drugs with interniMiate to
`high cli:;,.daricv. f he jar rnotii.1
`ei.(7hisive use
`inoderink;.1 A unifying model of ht,panc
`inadon, th(.:
`nli(lo is conistecit
`and ev.
`1)Iair6 the functionin of all eting
`of disposition
`by the
`ho Rvev,,?r. the equiitions are too complex for
`in (heir
`aprlicatioti and. 3.re hcA.
`
`The organ elear3 oct.. tyloi.it+, provide ;let-I:nil ions for
`gtlitTal Ck,vAnce t(stffili. SySIeMiC deatanCe
`reflect., any situation in, ,vhieh drug is admiokteredIvithout
`it, irtUy pa.4-ssing thtough the c.:learirg organ. Inifavenow,,,
`intramactilar, bucc)11. and uI.enus iìJì ejf. drugs
`ywhl, plasma concentrailoh-tinie (:bta go;Tmeii by
`
`'
`
`1.i(4 2-14
`
`bc
`
`pro:
`
`tArtlitl
`
`(11C.:
`
`Uf ail organ
`
`bjert to enzymatic degradation in bk.W3d , the upper
`(iri.4.;f',
`limit or CL it', of course-
`for this' biorransformation
`process.
`Thy intrinsic cle,arance is: a related, complementary refill,
`thdi ritilects the inaximuill metabolic or tra.nsport capahit-
`ity nt the clearirig ()ma n. h can be measured by-
`the drug irao th t? cireuhltirin feeding the clezt-
`ing organ, OraL intraperitoneal,. and, in pan, rectal dose
`place the drug directly into the liver via the mesenteric cft
`t1W drug is fully absorbed fron the administration site
`- i and undergoes biotransfeirmation entirely by the
`liver, then
`
`(Eq. 2-17i
`
`01: ov31 drise i:learauce, pwvides the intrinsic
`cleArance unctirtiMed lOr protein binding
`The V.:
`from in vitro drug metabolizing sytems can he
`used t:£1 predict teasonable
`of E,; for pi7rfused ritgan
`1u
`ilisposition of various drugs. 'The pharmaceutical industry
`UM es such technique=-; ro screen ne've compinirlds 1.0 deter-
`mine rnetaboli( patt.s and rate as Awn as potential for
`(IMF: interactions.'
`The tole of plasma protein bindilig in affecting organ
`clearance is only pard accounted for by the f
`term in
`Tlrit)rLS 2-12 and
`Experimeryral data for relationship
`ni
`according if) Egtiation 2-12 are depicted in Fig-
`t1
`ure
`compounds vviol
`ntn.nsc dea.rance such
`
`Lei
`
`,
`
`o
`
`o
`
`mor.....mwmompinv.a.non.erniram.
`Propferiolol
`
`Pherr.,4(..:qn
`
`;.4
`
`hi
`
`0,5
`Pravtion uni)onnd
`
`1.0
`
`vhere the upper limit n removal of drug from the body
`ch nn blood
`r:an tit,' perceived ).0; thi' 'i.311 Y
`For
`
`Figure 2-6 Effect of p3-).517, protein E.,:nding 0 n hepatic ,-..»,;trac,-
`tion of drugs with low (warfarin, intermediate iphenytoirl. and
`high (propram*M intrinsic clearance values. Adapted from
`Shand et as,"7
`
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`
`Page 7
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`

`

`16
`
`Basic Concepts and Principlos
`
`as warfarin, the En and Cl.ki are linearly dependent on
`This pheriomenon has heen terni ed "restrictive" clearance.
`proprano4 allow total
`ligh-clearance compounds such
`I or CI.n Q. wi'en
`he pat ic extraction ,vith En
`very high ("nonrestrictive" clearance).
`phenytoin k imermediate in befiztOor
`A compound
`in tbe perfuser/ rat ihr systern. What must occur n reanly
`r non reqrietive. compounds is that the rate of dissociation
`or the drng-protein cornre.x must be relative/y rapid in
`relation to Íe ranSit 1.1It.' of tirin thiongb the irn 'Fne
`to inathematically
`require a more comple:\
`process: and development of tribut
`account for th us kint.tt
`fundamental principles related to the mie of protein bind-
`organ drug uptake remains nl iflte'VeSt. S nihr eorn-
`tiptRke iI
`plkations permit.) to the rote ot 1-ed blOOd
`nie tiver
`flde0Se Of drags in ulatioik to organ u.;:rinsit nn.
`appears ti be capible art:Ku-acting drtigS frontboth plasma
`the kidney has access nnJv to
`and red blood cells,
`drugs In plasma.
`
`Renal Clearance
`A second elearinp, process can he ií1t1 to the mi ciel show;
`in Figure 2.2 to rel:resent renal clearance iwhich is always
`tiod d ii,posi tion stud-
`0 type of systernic clearance in
`/05. One relationship [bat dermes Mi:UV (if the ci:mir:cm
`fdcturs affecting
`u.To
`
`1--
`
`Eig, 2.. t9)
`
`The °tai tri IV WC ratio yield:; th c systemic avaìtbllby
`
`'
`
`AUC
`
`D .-: ALI(:
`
`(Eti. 2-2W
`
`A noncoMpartniental p,arafflOer for Chwac115:5rizing ab-
`indicawd by S name:
`hì
`sorption rate
`0arameter represents the avttragc durution &t rime thal
`drug nccuJt persisa in the dosage fortn and ,gas,trointes-
`art'
`tract. Drug o.bsorption tao:, constants, ik..
`riflai j,..nt)
`leasT sectire uf conventionally calculated phar-
`macoknit(ic paranicters because. of the compications it .
`curreci by incompli7te relcaw of drug &on) the drmage
`form, instability ía Gi contents (1:0), irrepulor absorption,
`(14) and Dater dolution
`mixed
`lag
`rates, effects of c:hanging Gi motility and contents. GI
`blood flow vtici:e. rust-p6y, eflect, blurred exponeii0;.11
`und poor
`equations. illadequate blood tr
`ternis i
`model specificity» The mAT provides a quawitative pa-
`rameter that hasic simitnariTes: flow long, t'Ili average,
`drug molocules ;-etrtaitt unabsorbed. b is calcufaced as-
`follows for a /Dl-Y-clearance dnig:
`
`AIRT,
`
`(Hl. 2-21)
`
`f
`
`(),,,
`
`Ci
`
`1:1
`)
`
`I?,
`
`I
`
`Wq.
`
`1,v/wre the