InternatiortalJournaLofClinicalPharmacolctgy,Tberapy
`
`andToxicolog),, Vol.27 No.1 1989 (179 2l I )
`
`The absolute oral bioavailability of selected drugs
`\( K. SrBrsBlre
`
`The Procter and. Gamble Cornpany, Miami Valley Laboratories, Cincinnati, Ohio 45239, USA
`
`Abstract. Oral bioavailability is best defined as the rate and extent to which an active drug
`substance is absorbed and becomes available to the general circulation. This concept is
`discussed, along with several popular methods for determining absolute oral bioavailability.
`The absolute oral bioavailability of numerous drugs is reviewed and interspecies comparisons
`are made. In general, absolute oral bioavailability does not correlate well between species,
`though relative comparisons might be made.
`Key words: absolute oral bioavailability - absorption - pharmacokinetics - metabolism
`
`Introduction
`
`The term bioavailability has a variety of defini-
`tions and for this reason it is important that it be
`defined in whatever context it is used. According to
`'Wagner
`11.979), the FDA originally defined bioavail-
`ability as the rate and extent to which an active drug
`substance is absorbed and becomes available at the site
`of action. In contrast, reahzing the difficulties in
`measuring drug at the site of action, the American
`Pharmaceutical Association defines bioavailability as
`the rate and extent to which an active drug substance is
`absorbed and becomes available to the general circula-
`tion. The latter definition is of more practical use
`because it permits a fairly simple experimental deter-
`mination to be made. Recently, the FDA has consid-
`ered adopting the American Pharmaceutical Associa-
`tion's definition. It is important to note bioavailability
`is not just a property of the drug itself, but also of the
`formulation in which the drug is delivered.
`Two types of bioavailability will be discussed
`here. Relative bioavailability is a comparison of the
`extent and rate of absorption and systemic availability
`of a drug from two different dose forms and some-
`times in comparison to t.wo different routes of
`administration. Absolute oral bioavailability is a spe-
`cial case in which the extent andrate of absorption and
`systemic availability of an oral dose is determined
`relative to an intravenous dose. This review deals
`strictly with the concept of absolute oral bioavailabil-
`ity and how it is measured.
`
`A distinction should be made between absorp-
`don and bioavailability, because the terms are often
`incorrectly used interchangeably. For the purpose of
`this discussion, absorption is defined as the drug
`passing from the lumen of the gastrointestinal (GI)
`tract into the tissue of the GI tract. Once into the
`tissue, the drug is considered absorbed. On the other
`hand, for a drug to be bioavailable, it must reach the
`general circulation intact. This is more of a challenge,
`because once the drug is absorbed it must still pass
`through the GI tract tissue, the liveE and the lungs
`before it reaches the general circulation. First-pass
`metabolism or elimination [Pond andTozer 1984] in
`any of these three tissues may destroy or remove a
`portion of the drug which was absorbed and there-
`fore, reduce the drug's bioavailability. Therefore, on a
`quantitative basis, the difference between absorption
`and bioavailability is that amount which is removed or
`destroyed by first-pass elimination or metabolism. It
`is possible for a drug to be completely absorbed, yet
`be entirely destroyed or removed by first-pass
`metabolism or elimination, so that its absorption is
`100% but its oral bioavailability is 0%. Earlier work
`on this concept was conducted by Harris and Riegel-
`mann [1969] using the metabolism of acetylsalicylate
`in the dog as a model. The concept is more elegantly
`presented in the pharmacokinetics handbook by Rit-
`schel [1986].
`
`Methods for determining absolute oral
`bioavailability of non-prodrugs
`
`Received N'[a1, 16, 1988.
`lleprint rcqucsts to Dr. 'iil K. Sietsema, Norwich F.ilton
`Pharmaceuticals, A Procter lncl Gtrmble Company', Woods Corncrs
`Laboratories, Nonvich, NY 13815, USA.
`
`By far the most popularly used method for determining
`absolute oral bioavailabiliry is what will be re{erred to here as the
`blood area under the curve (AUC) method. For this method, a drug
`is administered intravenously and orally and the concentrations of
`drug in blood (or plasma) are measured at numerous time points.
`
`Hopewell EX1078
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`180
`
`Sietsema
`
`f
`
`-
`
`(Equation 2)
`
`(Equation 1)
`
`(Equation 3)
`
`Thc arces unrler thc conceltretion time. curvcs are cletcrnrined (for a
`cliscussion of AUC calcrrlation nrcthocls, sc.c Ritschel [198a1) and
`absolutc' oral bioavail,rbilitl, is c,rlculetcrl accorclins to t]re following
`cquetion:
`l,l,,o.l AUC,,,, DOsl i,
`_
`f
`bloocl AUC;,
`DOS[,,,,
`rvhere F is absolute oral hioavailabilitl.ancl thc dose is exprcssctl on
`a pcr botlv nt. basis. Thc ratio term for the doscs allo\\.s onc ro
`mahc a line:rr corrcction if thr: oral antl intr;rr.enons closc levels rverc
`diffc'rcnt. It is also possible to corrcct the absolute oral bioavailabil-
`itv for diffr:rcnces in heli life fGibaldi ;rncl Perricr l9[i2], in r.hich
`case the equation is:
`blood AUCro DOSEi,
`_
`HL,,
`DOSE|,, HLo,,
`hloocl AUC;,
`This corrcction ACCoLlnts for cliffcrcnces in thc rxtes of elimination
`rhcn the rlrug is aclministr:rcd br, thc trvo differc-nt routes tGibaldi
`anci Perrier 19821.
`'['he blootl AUC methocl is generally the methoc] ol choice for
`determinaton of c[rug avai[;rbilit1, to t[]e gencral comparrrnent
`bcciruse it mcf,sures clrug clirectly rvithin the svstcmic circulation. It
`is nrost rccuratc for thosc drr-rgs r.hich arc distributccl 1;rrrely within
`thc centr:rl colrrpartlnent. For clrugs with a largc volume of
`c{istribtrtion, it is lcss accllrare, anrl shoulcl bc usecl rvith caution.
`Alothcr nrethod wfiich is less commonlv usecl is thc urine
`clrug excretion nrethod. This nrethod is sirrilar to thc bloocl AUC
`mct]roal, excL'pt that the clnrq conucntrrri, ,n ir nt..aru recl jn urinc
`insteacl of bloocl. This mcthocl l-ns thc aclvantrgc tlrat it is
`noninvasive.'Io r'lctcrnrine absolute oral bioavailabilitv bv the urilr.
`clrug excrctiorr nrethod, the clmg is aclministerecl intravenously ancl
`orally lncl urinc slmples are collectcti until the tlrug has bccn
`substrntiallv c.liminatecl. Absolute oral bioer.ailabilitv is then calcu,
`htet{ to the equation:
`urine AUCp"
`x DOSEi,
`n ,
`urinc AUC;,
`DOSE',,
`C)ne of tlre cliserlvanteges of thc urine clrug cxcrction method
`is tlrat its usr:fulncss is lirnitccl to rhose drugs for u.hich significant
`quartitics o[ intact clrug are elininetcd in the trrine. It should be
`trsccl l.ith c.trtion for rlrtrgs u.hich arc eliminatccl onlv in small
`f,rnoLnrts il thc trrine, due to the inherent crror involvcd in trr itrg t.,
`mcf,sLlre srnlll differences Lrctrveen srnall numbers. Since hithly
`lipophilic clmgs in gcnertrl:rre not eliminatcd in the urinc due to e
`high level of plasrnr protein bindint, tbe urinc clrug exer.tit,n
`nrethod is gcner;rllv not useful for highlv lipophilic drugs. Thc
`bloocl AUC mcthocl shoultl bc usecl ilstcad.
`Thc AU(l rario mcthocls clcscribc.d above may elso be appliccl
`to otlrer body fluids, such as salir.r fSalui ct al. 198]1. As rvith thc
`urile clrug r:xcretr'on methoti, this rnethoc] has thr: aclr.entage of
`being noninr.asive. Hos.ever, thc use of saliva and other boc{y flr-Licls
`bcsicles bloocl is onlv r-elic1 if intect drug is founcl therc. in significant
`allo Liltts.
`It is also prossible to nreasllrc bioavailabilitv of rr clrug not
`basecl on its drug concerlrrxtions in blood or urine, but on an
`obserr.etl pharrnacologicrrl rcsponse. This "pharrnacoriyrramic
`rncthod" may bc uscd if analytical proceclnres rrc nor avaihblc for
`thc drug. It assumcs that the :Lctiyc lorm is thc unnretrrbolizctl
`
`parent tlrue. The resultins pharrracologicrrl aveilabilitv nrav cliilcr
`somer.hat from absolure oral bioavailabilitv, clLre ro thc fact that
`therc is lot alt,avs a clirect linear rclatiorrship betrveen clrue
`concentration and effect. This concc.pt is discusserl in more cleteil by
`I{itschcl [198.1 and IgtZ]. It shoulcl bc notecl that the rncasurement
`of bioavailabilitv using r phannacological response cloes have thc
`rdvatrtagc oi'estirnating tire availability of the clrus to irs sire oi
`:rction, accor.lins to thc FI)A's original clefinition. Thcreforc, ii the
`goal of an inr.tstigation is to rnL.eslrre tire cffects oi different
`variables on the efficacy of a clrug, thc use oI a pharmrcolosical
`rcsponse me1, bg th. method of choice. Horver.er, the relcler shoulcl
`notc tllat nlcasLrl emcnts of pharnr:rcolotic;rl response arc olrten
`imprccise, ancl for this rcason, pharmacolo{icrrl ev:ilability meas
`Lrrements often h;rve a high clerree oi variabilitr,..
`
`In situations rvhcrc it is not possible to nlcasure intact clrug in
`blood or urine, it is possible to Lrsc the concentmrion of a rnetabolite
`to cstitn]tc the bioar.ailahilitv Oi the parent cornpound fWagner
`1972). For this calculation, the assumptior] is m:rtlc that rnctabolisnr
`of parcnt contpouncl ro the mctabolitc is thc same for eithr:r the
`intravenous or oral routes of administration. This shoulti be
`vrlidated prior to using this rnethocl, prrticularly if the drr:g
`unclcrgoes lirst-pass metabolism, becausc if the rnetabolite is
`procluced by lirst-pass metabolism, the absolr-Lte oral bioer.ailability
`r.ill be overestimated by this rncthocl.
`
`It should be emphasizcd tlut the methocls clc.scribed trbor.c for
`dctennining absolute oral bioavailabilitv are reall1, cstirnates, based
`on tlre assumptions tltxt thc voluntes of distribution, clcararrce r:rtes,
`and half lives for thc drug lre thc sanre following intrar-enous lncl
`oral ac{ministration. Thcsc cstimates also nra]re thc:ssurrptiols that
`thc clrug tloc's not exhibit saturable metrbolism rvithin the rtrngc of
`thc closes tL'stcd anLl that thc roLrtes of mr:tabolisrn arc constilnr as
`thc route of atLninistration is t,ariecl. lf any o1'these ilssunrprion\ rrr
`not rnct, tben thc cstimat;on of absolute orel bioav;rilebility bv these
`methocls mav be somewhat in error. A nunrber of investigators have
`proposecl rnodcls for rnorc acclrrAte tletr:rrnination of absolute oral
`bioavailabilitl, when these assurnptions arc not rnet fRubin and
`Tozer 19E4, Kn an errcl T;lI 1973, Collier and Ricselmen 1983].
`
`It is oftel desirable to cstilnate x.hat the rbsolute oral
`bioavailabilitl- might be, cycn though oral dosins clata are not
`ar.ailable. Accortling to the rncthocl of Gibaldi et a1. [1921], this can
`be clonc if one lssumcs that absorption is complete trncl that the loss
`of drug occurs onlv cltrc to first-pess metabolisnr in thc. lir.cr. It
`requires an cstinlate of thr: blootl flrv- rate to the lir.cr. Thc cqurritrn
`uscd is:
`
`F:
`
`a
`(Equation '1)
`Q + D/AUC
`where Q is the liver bloocl flow-, L) is the closr: aclministcrecl
`intraverrouslr., ancl AUC is thc area unclcr the intrxycnolrs conccn
`tration time curye ior intact clmg. For drugs vhich:rrc tlistributecl
`into thc plasnra (as opposecl ro thc bloocl cc.lls), a more accurate
`estimate mey be obtainecl if plesma concentrf,tions lre usccl to
`calculate the AUC anc{ Q is crpressecl as plasml flow rate rathcr
`than bloocl f1o\y rltc.
`
`2
`
`

`

`The absolute oral bioaoailability of selected. drwgs
`
`181
`
`Methods for determining absolute oral
`bioavailability of prodrugs
`
`Prodrugs lStella er al. 1985] present a special case for
`measuring bioavailability because the administered drug is not the
`active form. It would, therefore, be misleading to calculate the
`bioavailability according to concentrations of the intact prodrug in
`blood. It is preferable to measure the concentrations of the active
`form after administration of the prodrug by the intravenous and
`oral routes. The oral bioavailability could then be estimated using
`Equation 1. However, this may lead to an overestimation of
`bioavailability if all or a portion of the active form is generated by a
`first-pass mechanism. In this case, one should administer the active
`drug by the intravenous route and the prodrug by the oral route.
`The active drug should then be measured in blood or urine, and the
`oral bioavailability calculated using Equation 1. In this s/ay, the
`ammount of active drug formed from the orally administered
`prodrug is compared to an intravenous dose of active drug, which is
`by definition 100% bioavailable.
`
`Drugs with active metabolites
`
`In cases where the pharmacological activity of a
`drug is due to multiple circulating active forms,
`measurement of bioavailability becomes a tricky issue.
`In some cases, it has been possible to measure the
`concentrations and relative activities of several con-
`tributing metabolites fMarino er al. 1986]. However,
`this is an arduous task and it involves assumptions
`which may not be met. In situations such as this, it
`may be possible to use a single major metabolite to
`estimate bioavailability. A pharmacological endpoint
`may also provide a viable alternative Ior ..r.rrrr.i.rg
`drug bioavailability under these circumstances.
`
`Factors affecting the measurement of absolute oral
`bioavailability
`
`There are a .variety of factors which could affect
`the assessment of absolute oral bioavailability, and a
`detailed discussion of each would be beyond the scope
`of this review. More information on these factors may
`be found in the reviews by Ritschel l19\7a and b],
`Jollow and Brodie 11,972), Pond and Tozer 11984f,
`Melander and Mclean [19S3] and Bauer et al. [19Sa].
`Several of these factors will, however, be mentioned
`here as a reminder of the complexiry of biological
`systems.
`Obviously, various disease states such as hepatic
`failure may have major effects on absolute oral
`bioavailability. This will especially be the case if the
`drug undergoes first-pass metabolism. For a drug
`which is administered as the active form, hepatic
`failure would lead to decreased first-pass metabolism
`
`and hence increased bioavailability. However, in the
`case of a prodrug which is activated by first-pass
`metabolism, hepatic failure would result in decreased
`bioavailability.
`Strictly speaking, one would not expect renal
`failure to have alarge impact on absolute oral bioavail-
`ability, because the effect of renal failure should be
`similar, regardless of whether the drug was adminis-
`tered orally or intravenously. HoweveE if renal
`elimination is dose-dependent, renal failure may lead
`to an apparent change in absolute oral bioavailability if
`the amount of drug delivered to the systemic circula-
`tion following intravenous dosing is different than the
`amount delivered following oral dosing.
`The rate of drug dissolution and drug absorption
`are important determinants of bioavailability [follow
`and Brodie 1,972), panictiary for drugs which
`undergo saturable first-pass metabolism. It follows
`that characteristics of the gastrointestinal tract such as
`motility, pH, feeding state and the presence of bile
`salts would have an effect on drug bioavailability. It
`would, therefore, be expected that altered GI function
`may have an impact on bioavailability. This will
`especially be the case for drugs which undergo first-
`pass metabolism within the GI tract tissue.
`Diurnal variation may have an impact on the
`measurement of absolute oral bioavailability. It has
`been reported [Bauer et al. 1184) that such diurnal
`changes in bioavailability may be due to diurnal
`changes in drug clearance, among other things.
`
`Absolute oral bioavailability - a review of the
`published data
`
`For this review, absolute oral bioavailal:ility data
`on over 400 drugs was collected. The data are shown
`in Thbles 1 and 2. By fa4 the bulk of the information
`collected has been obtained in man, but some data are
`available for experimental animals as well.
`The absolute oral bioavailabilities in man range
`from near zero (buspirone, cephacetrile, cephalothin,
`cephapirin, cimetropium bromide, coumarin and
`isoproterenol) to complete (amosulalol, caffeine,
`cephalexin, diflusinal, ethosuximide, indomethacin,
`minocycline, pentobarbital, piroxicam, practolol,
`probenecid and trimethoprim, to name a few). How-
`ever, most drugs are somewhere in between. Figure 1
`shows the frequency distribution of the absolute oral
`bioavailability of drugs in humans. Surprisingly, the
`distribution is quite flat, but skewed slighdy toward
`complete bioavailability. It should be noted that this
`population of data is almost certainly biased, since it
`represents only those data reported in the literature.
`There might be numerous drugs whose development
`was abandoned due to low bioavailability, and for
`
`3
`
`

`

`182
`
`Sietsema
`
`-fab/e l. Pcrccnt absolute oral bioavailabilitv of drugs. Absolute oral bioevailabilitv has been determinecl for these drugs by comparison of
`
`cotrcentrations of the unconvertcd pnrdrug.
`
`lloclents f)ogs
`
`Primates N'Ian
`
`Rcicrcnccs
`
`37+12
`72+11
`
`92+c)
`
`,16 6E
`
`74
`15 50
`
`36 96
`75 -93
`9O+9
`
`SS
`9i6
`95+5
`22 86
`
`lJenet et al. 198'1, Nleier 1982
`Arnlie et al. 1979, Clements et al. 1984,
`Dir.oll ct al. 1982. Forrest et al. 1982
`Henclerson et il. 1977
`Misra et al. 1980
`Karnath et al. 1981, Strong et al. 1975,
`Jacobi r:t al. 19133
`Harris antl RiegeLnan 1969, hvamoto et trl. 1982,
`Needs anrl Brooks 1985
`Peclersen ancl FitzGeralcl 198.1
`Simon ct al. 1976
`Krasnv et al. 1981, Leskin 19{J3,
`Petersluncl et al. 198,t
`Tcste ct al. 1978, Verbeeck et al. 1981
`Houin ct al. 198,{
`Breithaupt and Tittcl 19u2,
`N{urell ancl Rapeport 1 986
`Smith et;rl. 198,1
`[ohnsson ancl Regardh 1926
`Benet et al. 1984
`Latini et al. 198'1, Pourbaix ct el. 191J5,
`Riva et al. 1982
`Pond antl Tbzcr 191J.1, Schulz et al. 1985
`Faulkner ct al. 1986
`Nakashima et el. 198,1
`Arancibiaetal. 1980,Spyherctel. 1972
`Benet et al. l9E4
`Ehrncbo ct al. 1979, Tlnigarvara et al. 19t2
`Parh et al. 1983
`Paxton 1986
`Bcnct et al. 19{J4
`Fitzgcralcl ct el. 1 978, Johnsson and
`Regarclh 1976, Mason ct il. 197c)
`l\'leier 1982, Wan et al. 1979
`l0
`Bratcr ct al. I9E3
`59- 128 Thvlor ct el. 1987
`Workman i:t al. 1984
`Benet 19t5
`\Tarrington et al. 1980
`Grimeldi e t al. 19{J6
`Grrrett et al. 1982, Rapcport 19135
`Schran et al. 1985
`Ilrodie et a[. 1986
`Jochemsen et al. 1983 a ancl b
`Ryc.rfelclt ct al. 1982
`(llissold et al. 1987
`f)irver et ai. 1982, Tschopp ct al. 1978
`Holazo et al. 19E,1. Lau et al. 1986
`Bcnct ct al. l91J'1
`Garnmans et al. 1986
`llutz et al. 1985
`
`46+9
`52 - 88
`100
`9l+10
`<10
`62+17
`93+12
`
`85 95
`54+ 12
`
`60
`90
`3l +-5
`12-37
`
`49
`7A+22
`11+4
`50-80
`.16+15
`66+11
`(r0 80
`3
`
`f)rug
`
`Acebr-rtolol
`Acctarninophen
`
`Acetvlrrethtrdol
`Acctl,lnorrncthadol
`Acctl,lprocainamiclc
`
`60+8"
`
`{J'+ 100'
`
`76+2t'
`
`Acetyls;rliq'late
`
`15"
`
`45+8
`
`Aciclocillin
`Acvclovir
`
`Alclofc'nec
`AJizapricle
`Allopurinol
`
`Alprazolam
`Afprenolol
`Amantadine
`Arniodarone
`
`Arritriptvline
`Amloclipine
`Anrosulalol
`Arnoxicillin
`Arnphotc'ricin B
`Ampicillin
`Arnrinonc
`Amsacrilc
`Aprinidine
`Atenolol
`
`Azosemide
`llenzidamine
`lJenznitlazole
`Bcpridil
`Bctexolol
`f]iperiden
`Ilretyliunr
`Bronrocriptine
`Brornopridc
`Brotizolanr
`Iludesonide
`lluflomerlil
`Bufur.rlol
`Btrnretenidc
`Bupropion
`Buspirone
`Butvlrrorphine
`
`80 90
`
`8{J'
`
`90+10'
`
`130
`
`6^
`
`10"
`
`4
`
`

`

`Tbe absolute oral bioaoailability of seleaed d,rugs
`
`183
`
`Thble 1. Percent absolute oral bioavailability of dnrgs, continued
`
`Rodents
`
`Dogs
`
`Primates Man
`
`References
`
`Blanchard ancl Sawcrs 1983
`Bccrmann ancl Groschinshy-Grind 1980
`Duchin et al. 1 982, Singhvi et al. 1 98 1
`Benet et al. 198,1
`Benet et al. i984
`Obach et al. 198,{
`\(/orl<man et ai. 1986
`Benet et a1. 1984
`tr{arino et al. 1 9u2
`Brogartl ct al. 1 978
`Benet et al. 198.1
`Pfeffer et al. 1983
`Benet et al. 1984
`Benet et al. 198.1, Fix et al. 1986
`Benet et al. 198.1
`Foorcl 1976
`\Villiams and Harding 1984
`Brosard et al. 1928
`Schneicler et al. 1978
`Brogard et al. 1928
`llrosarcl et al. 19ZE
`Brogard ct al. 1978, Philipson ct al. 1987,
`Rattie et al- I 976
`N{roszcak et al. 1928
`Nervell et al. 1983
`Ambrose 198,1, Kau{fnran et al. 1981,
`Krarner et al. 1984, Nahata and Powell 1981
`
`Ambrose 19lJ,l
`Creenblart et al. 1978
`Blaschkc and Rubin 1979, Pcntikainen et al. 1 978,
`Pontl and Tozer 1 984
`Aclerounmu et al. 1987, Gustafsson et al. 1983
`C)sman et al. 19112, Resetarits and Bates l9Z9
`Athanikar and Chiou 1979, Huang et al. 1981 and
`19S2, P.rton rrr,l Web'ter 1985
`Benet et al. 1984
`Huupponen and Lamrnintausta 1981
`Roaflaub 1 975
`Irebre et al. I 971
`Beermann and Groschinsky-Grind 1980,
`Fleuren et al.1979
`f)ubruc et al. 1 987
`Arancibia et al. 1985, Bodemar ct al. 1981,
`Okolicsanyi et al. 1982, Richartls 1983,
`Somog,vi and Gugler 1983, Sornogyi et al. 1980
`
`Lnbimbo et al. 1986
`Lane irnd Levv 19{J3
`Hoffken et al. 1985
`Van Pecr ct al. 1 987
`Bolton et al. 1986, Davies et al. 1985,
`Nilsson-Ehle et al. 1985
`
`100
`
`100
`
`62
`
`70
`<10
`
`9A
`78-90
`80-100
`96+3
`55 -77
`<10
`
`78
`<10
`
`1.
`
`23 -44
`0
`
`1.20+1.6
`
`0 0
`
`85+29
`
`93 -99
`73 -t02
`69+1,3
`
`80
`
`100
`
`1.2+3
`
`89-98
`33-56
`25 -44
`
`32+1.9
`
`118
`4t+21.
`25 -30
`64+t0
`
`100
`60+ 10
`
`2+1
`
`63 -77
`40 50
`3t 99
`
`J5 791
`
`39 -594d
`
`88
`4A+7
`
`8+2
`
`69',
`
`11+8'
`
`z0+18
`30 50
`
`Drug
`
`Caffeine
`Canrenoatc
`Captopril
`Carbamazepine
`Cerbenicillin
`Carbidoptr
`cB,1951
`Cefackrr
`Cefaclrox il
`Cefalexin
`Cefamandole
`Ccfatrizinc
`Cefoperazone
`Cefoxitin
`Ccftaz-idirnc
`Cc'furoxime
`Cefuroxime Axetil
`Cephacetrile
`Cephalexin
`Ccphakrthin
`Cephapirin
`Cephracline
`
`Chloprcdnol
`Chlorambucil
`Chloramphenicol
`
`CI.rloramphen icol
`Palmitetc
`Chlordiezepoxide
`Chlorrnethiazole
`
`Chloroquine
`Chlorothiazidc
`Chlorphenirarnine
`
`Chlorpron-raz-ine
`CLlorpropamide
`Chlorprothixene
`Chlortetracycline
`Chlorthaliclone
`
`Cicloprolol
`Cimetidine
`
`Cimetropinll
`Bromide
`Cirrrom itl e
`Ciprofloxacin
`Cisepridc'
`Clavultrntrte
`
`5
`
`

`

`184
`
`,Sietsema
`
`Thble 1. Percent absoiute oral bioavailability of drugs, continued
`Primates Man
`
`Rodents
`
`Dogs
`
`Drug
`
`Clindamycin
`Clofibric Acid
`Clonazepam
`Clonidine
`Cloxacillin
`Codeinc
`
`Coumarin
`Cyclobenzaprinc
`Cyclophosphamide
`
`Cyclosporine
`Dapsone
`Dcmcthylchlor-
`tetracycline
`Depamide
`Desipramine
`I)examethasone
`
`I)extromethorphan
`f)extropropoxyphene
`Diacetolol
`Diaz-epam
`
`I)iclofenac
`Dicloxacillin
`Diflunisal
`Digitoxin
`Digoxin
`
`Dihydrocodeine
`Dihydroergosine
`Dihyrlroereotamine
`I)ihydroergotoxi n e
`Dilantin
`Diltiazcm
`
`Diphenhvdramine
`
`Diplrridarnole
`
`Disopvramide
`
`Dixyrazine
`DN-1412 (Pepticle)
`Domperidone
`Doxaprarn
`Doxazosin
`Doxepin
`I)ox,vcycline
`Droloxifc'ne
`
`z4 1 1 8',f
`
`2A 6a
`
`4^
`
`75^
`
`45+16
`
`7a
`
`147+9
`
`12+8
`
`74 - t)a
`
`85
`
`98+31
`87 -96
`37+13
`55+5
`
`3+3
`52
`9a 96
`
`20-50
`93+8
`
`66
`68+23
`33-68
`53+41.
`
`29 -70
`36+5
`98+6
`
`58+14
`49+tl
`100
`84-93
`68+13
`
`t2-34
`10+3
`52+1,4
`5-12
`1.02
`24-94
`
`58+1.2
`
`52+23
`
`25
`
`7A
`
`10
`
`OU
`
`1"
`
`50'
`
`5+lb
`
`83+11
`
`10+8
`
`t4
`6t+1,9
`65+14
`t3-45
`93
`
`References
`
`Benet et al. 1 984
`rValmsley 1984
`Al-Thhan et al. 1.984,Beuer- et al. 1984
`Davies et al. L977 and L978
`Nauta and Mattie 1976, Spino et dI. 1.984
`Butz et al. 1985, Hull at al.7982,
`Pond and Toz-er 1 984
`Pond and Tozer 1984, Ritschel et aL.1979
`Hucker et a,1. 1977
`Grochow and Colvtn 1979,
`\flagner and Fenneberg 1984
`Ptachcinski eT- al. 1985
`1986
`^nd
`Pieters and Zuid ema 1987
`
`^1.1984,
`
`Fabre et al. 7971
`Bialer et a.l. 1987
`Benet et al. 1 984
`Brophy et al. 1983, Chalk et al. 1984, Eadie et
`Rose et al. 1981,'Workman et al. 1986
`Dixon et al. I978
`Pond and Tozer 1984
`Flouvat et al. 1981
`Divoll et al. 1983, Locniskar et a,l. 1,984,
`Loscher and Frey 1981, Ochs et al. 1982
`Brune 1985,'$?'illis et aI. 1980
`Doluisio et al. 1969, Nauta and Mattie 1975
`Verbeeck et al. 1983
`Yohrrnger et a.l. 1977
`Brumbaugh et al. 1983, Doherty et al. 1984,
`Hager et al. 1981, Pedersen et al. 1983
`Rowell et al. 1983
`Cvelbar et al. 1987
`Little et al. 1982
`Voodcock et al. 1982
`Doluisio 1972
`Hermann and Morselli 1985, Hermann et al. 1983,
`Kohno et al. 1977,Leonard and Thlbert 1982,
`Ochs and Knuchel 1984, Thlben and Bussey 1983
`Blyden et al. 1986, Carruthers et al. 7978,
`Paton and \Tebster 1985
`Bjornsson and Mahony 1981, Nielsen-Kudsk
`and Pedersen 1 979
`Bryson et al. 1978, Haskins et al. 1980,
`Karim et al. 1.978, Ltma et al. 1984,
`Siddoway and \Woosley 1986
`Liedholm et al. 1 985
`Jokohama et al. 1984
`Heykants et al. 1981 .
`Robson and Prescott 1978
`Kaye et al. 1986, Vincent et al. 1985
`Benet et al. 1984
`Frbre et al.1971.
`Janzen et al. 1987
`
`6
`
`

`

`The absolwte oral bioaoailability of selected d.rwgs
`
`18t
`
`Thble 1. Percenr. absolute oral bioavailabiliry of drugs, continued
`
`Drug
`
`Enalapril
`Encainiclc
`Endralazinc'
`Iiphedrine
`Eproxincline
`Ergotamine
`Erythronrycin
`Estradiol Valerate
`Ethanbutol
`[,thenzamide
`Ethimizol
`Ethylrrorphine
`Ethl,nvlcstradiol
`
`Ethosuximide
`Etilefrine
`Etofylline
`Etoposidc
`Farnotidine
`Feloclipine
`Femoxetine
`Fenf[Lmizolc
`Fcnfluramine
`Fenoprofen
`Fenoximone
`Flavoxate
`Flecainidc
`Flucloxacillin
`Flucytosine
`Flunisolide
`Flunitraz-epam
`Fluocortolonc
`Fluorcsccin
`Fluorouracil
`
`Fluoxetine
`Flupcntixol
`Fosfomycin
`Frusemicle
`Furosemide
`
`Gitoxin
`G1:rziovine
`Glipizide
`GO-5,+3{J
`Griscofulvin
`Guanabenz
`Haloperidol
`Hexarnethl,lmelamine
`Hydralazine
`
`Rodents
`
`Dogs
`
`Primates
`
`Man
`
`References
`
`+J
`7 -82
`75
`
`70
`2-5
`30-65
`3+2
`77+8
`
`4 -22
`
`8+2
`
`641
`
`43+1.6
`
`76d
`
`18'
`
`o
`
`15"
`
`100+ 10
`
`55
`65 -95
`t7 -72
`37-45
`16+6
`5-10
`50
`89+10
`
`80
`
`53
`
`90
`
`95
`44-54
`89+ 10
`20+5
`
`78-89
`99
`0 -74
`
`40-55
`J/
`63+22
`63+9
`
`95
`
`100
`
`95
`
`65+1,4
`
`26-55
`
`19^
`
`1,7+7
`
`69^
`
`30"
`
`8'
`
`72
`
`91+ 8
`80 98
`
`50+18
`
`79+3b
`
`Dickstein 1986
`Gillis and Kates 1984. Poncl and Tbzer 198,1
`Meredith et al. 1983
`Nlarvola and Kivirinta 1978
`Achtert ct al. 1987
`Ibraheem et al. 1981, Perrin 19E5
`Mather et al. 19{J1
`Dustcrbcrg ct al. 1985
`Benet et a1. 198,1, Chen et al. 1984
`Shibasaki et el. 1 984
`Trlovec et a1. 1985
`tsutz et al. I 9E5
`Back ct al. 7979 md 1981, Hirai et al. 1981,
`Hunrpel et al. 1979, Newburger et al. 1983,
`Orme et al. 19lll
`Benet et al. 19E,1
`Hengstmann et al. 1925, Pond ancl Tbz-cr 198'l
`Zuidema et al. 1981
`D'Incalci et al. 1982, Stewart et al. 1985
`Campoli-Richerds ancl Clissolcl 1 986
`Batrrnhielnr et al. 19E6, Ilclgar et al. 1985
`Lund et al. 1929
`Vingc ct al. 1985
`Beckc'tt and Brookes 1962
`Rubin et al. 1922
`Alhen et al. 198,1
`Bertoli et al. 1976
`Gillis and Kates 198,1
`Benet et a1. 198,1
`Gutler et al. 1978, Daneshnrencl ancl Warnock 1983
`Chaplin et al. l9EO
`IJecherucci er al. 1985
`Taubcr et al. 1984
`Barry end Behrendt 19E5
`Cano et a1. i979, Christoplridis et al. 1978, Finch et al.
`1979, Phitlips ct al. 1980, Poncl anci Tbzc'r 198,1
`Benficld ct al. 1986
`forgensen 1 980, Jorgensen et al. 1 982
`Caclorniga et a1. 1977
`Cutler ancl lllair 1929
`lleermann ancl Groschinsky Grincl 1980,
`Grahncn ct al. 1984, Lee and Chiou 1983,
`Ogata et al. 1985, Smitb et al. 1980
`Hupin et al. 19l9
`Marz.o et al. 1977
`\fi/ahlin Boll ct al. 1982
`Heng1, ct al. 1987
`Benet et al. 198,1
`N{eacham et trl. 1981
`Forsman alcl C)hman 1976, Hollev et a1. 1983
`Klippert et al. 191J1
`Lr-rdclen et al. 1982, Pond ancl "[bze r 198,{,
`Thlscth 1 976
`
`7
`
`

`

`186
`
`Sietsema
`
`'[able 1. Iterccrr rbsolute oral bioaveilability of clrugs, contjnuecl
`
`Drug
`
`Rorli:nts
`
`Dogs
`
`Primates
`
`Man
`
`Rcferences
`
`Hl,droch lorothiazicle
`
`H.vclroflum ethiazid c
`Hvclromorphonc
`Hl,drox 1- b utvratc
`H l,clroxr.trvptophan
`Iicnproclil
`Ifosph anr i clc
`IJopr ost
`I nriprarninc
`
`Intlaparnide
`Inclobufen
`I ndonrcthlcin
`
`I ntcrfcron
`lso so rbitlc' clinitrate
`
`8"
`
`5-9"
`
`97
`
`64^
`
`0c
`
`Isosorbiclc 2 mononitrirte
`
`100"
`
`I sosorbid c--5 -rnor on itratc
`
`21
`
`50+38
`
`28 +3
`
`11+13
`
`25+12
`
`53"
`
`6/+d'l
`
`8 +2"
`
`28 .+s".'
`
`5 121'
`
`75+ 18
`
`Isoproterenol
`lsotreti n oin
`Ketarninc
`Ketobcrnitlone
`Kctoconrzole
`Ketoprolcn
`Khellin
`Labctakrl
`
`Leucovorin (l)
`l.euconrrin (d)
`Lcvodopl
`Lcr.onorqestrel
`
`L.idocainc
`
`Lisuride
`Lithiunr
`Lorazcpem
`Lorcr in irle
`
`Lormet.Izepanl
`Xlaprotilinc
`Nlcbcndazole
`Nlccillinem
`tr{r'droxelol
`
`Xl[efloc1u in c
`
`J\'lelph;rlan
`
`72+ 17
`
`50
`
`52
`
`17 81
`
`85 100
`16+ 1
`17+27
`
`85
`1J5 122
`
`5
`.+7 -58
`
`100
`
`9l+18
`
`0
`
`17
`34+ 15
`
`E5
`
`30+3
`
`c)7+16
`19+ 1
`l5
`87+9
`
`34+12
`
`150
`95+5
`61 ta9
`35 65
`
`70-t0
`36 67
`D.
`
`5
`42 -82
`85
`72+23
`
`Barbhaiya et al. 1982, Beermann ancl
`Groschinslq. Grinrl 1980
`Bccrmann antl Groschinsky Grind 1980
`Vallncr et al. 1981
`Lcttieri ancl Fung 1976
`N'Iasnussen ancl Niclsc'n-Kudsk I 980
`Durancl ct al. 1987
`NIcNiel ancl N'lorgan 1981
`Kruuse ancl Kreis 198(r
`Abernethv r:t rl. 198,1, George 1929,
`Nag1, 3n.l 1,,1r"t sson 19l5, Poncl ancl Tirzer 19E'1
`Crebow rnd Treitmau 1981
`Fucella et al. 1929
`Alr.:rn et a|.1975, Bhat et al. i9E0, Brunc 198-5,
`Ogiso et al. t983, \-eh 19s5
`Benet et al. 198.t, Wagner 1922
`Ilogaert 1 981, Pond lnc{ Tozer I 98'1,
`Strechl ancl Geleazzi 1 985
`Lcitolcl encl l-auien 1983, Straehl and Caleu.zi lc)85,
`Straehl et al. 1 984
`N'laioretal.1984,Steucleletal.l98i,
`Straehl and Gtleazz-r 191i5, Strer:hL ct al. 19E'l
`Poncl ancl 'lizer 19E'1
`Cotler et al. 1 981
`Clements et al. 1982
`Anclerson et el. 1982
`Ilaxtcr ct el. 19t6
`[ulou et a].1976, Vcrbcech et al. 19t3
`Saic:l 19E2
`Bloschke and Rubin 19l9. I)ancshmcntl nd
`Robcrts 1982 end 19ll'1, Elliott r:t al. 1984,
`Horncida c't:r1. 19l8, Louis ct el. 19l8, tr{eier 19E2
`Stran- et al. 19E't
`Straw et al. l 9E-1
`Cotler et al.1976, Sasrhtrra et al. 1980
`Back et rl. 1981, Gomnraa ancl Osrnen 19113,
`Htunpcl et il. 1978
`BhscLke ancl Rtrbin 1979, Cusacl< et el. 1985,
`cle []oer et el. 1979, George 1929, Pontl anrl
`Tozer 198,{. Ritschel 1987
`Hr-rmpcl ct al. 19E1 ,rncl 19,9.+
`Bcnct ct al. 198,1. Ritschcl 1987
`Greenblatt 1981, Greenblatt et al. 1979 antl 1982
`Georgc 1979, Gillis end Kates 198.1,
`Klotz ct al. 197E and 1979. Pond urd Tbzer I 984
`Grccnblatt et al. 1983
`Bcnct et al. 198.1
`I)arvson et al. 1985
`Roholt et al. 197-5
`Elliott ct al. 198.1
`lil1hitr: 198.5
`Bosanquet arrcl Cilbr. I982, Reece et al. 19E6,
`V/oorlhousc ct al. 1983
`
`8
`
`

`

`Tbe absolwte oral bioaaailability of selected drugs
`
`187
`
`Thble 1. Percenr. absolute oral bioavailability of drugs, continued
`
`Rodents Dogs
`
`Primates Man
`
`References
`
`Drug
`
`Menogaril
`Mepindolol
`Meptazinol
`Mercaptopurine
`Metergoline
`Metformin
`Methacycline
`Methadone
`
`Methimazole
`Methotrexate
`
`Methotrimeprazine
`Methoxsalen
`Methyldigoxin
`
`Methyldopa
`
`Methylergometrine
`Methylphenobarbital
`Methylprednisolone
`
`Methyl Proscillaridin
`Methysergide
`Metoclopramide
`
`Metopimazine
`Nletoprolol
`
`N{etronidazole
`
`N{exiletine
`N{ianserin
`Nliconaz-ole
`Ntidalcipran
`Midazolarn
`
`Milrinone
`N{inocycline
`Moclobemide
`Molsidcxninc
`N{orphine
`
`N-acetvlcysteine
`Nadolol
`Naicillin
`Nafthazone
`Nalbuphine
`
`3o.l
`t-2'
`
`40
`
`12+51'
`
`100"
`
`100
`
`49 91^
`
`48
`
`59 100
`
`31"
`
`3+1"
`
`66
`2-8
`
`82+11
`2 2a
`16t 11
`23+5
`50 60
`58
`79+21
`
`93
`36-88
`
`33 74
`
`41 - 83
`
`26+15
`
`60
`73
`49-81
`
`59
`13+4
`73+25
`
`19+8
`50+11
`
`McGovren et al. 1984
`Bonelli et al. 1980, Krausc and Kuhne 1983
`Franklin and Aldrige 1976, Norbury et al. 1983
`Pond and Jbzer 198.1, Zimm et al. 1983
`Martini ct al. 1981
`Pentikainen et a.I. 1.979, Sirtori et al. 1978
`Fabre et al. 1 971
`Gourlay et al. 1986, Meresaar et a1. 1981,
`Nilsson et al. 1982a and b
`[ansson et al. 1985
`Campelletal. lgE5,Christophidis etal.1979,
`Harvey et al. 198,1
`Pond and Tbzer 1984
`Krelrter and Higuchi 1979
`Boerner et al. 1976, Hintlerling er. al.1E77,
`Rietbrock et al. L976
`Barnetrer al.1977,Dobrinskaetal.1982,
`Myhre et al. 1982
`Mantyla and Kanto 1981
`Hooperetal.1981
`Antal et al. 19E3, Green et al. 198.+,
`Narang ct al. 1983
`Belz ct al. 1')76
`Bredberg et a1. 1986
`Bauer et al. 1984, Graffner et al. 1979,
`Kapil et al. 19E+, McGovren et al. 1984,
`Ross-Lce et al. 1981, Thm et a1. 1981,
`Vright and Pitts 1984
`Gaillot et al. 1982
`Hogstedtetal.lgE5,JohnssonandReeardh lgT6,
`Johnson et al. 1975,Jordo et al. 1980, Meier 1982,
`Regardh et a1. 1981
`80 100 Houghton et al. 1.979, Mattila et al. 1983,
`Neff-Davis 1981, Robin et al. 1980,
`Shaffer et al. 1986, Thicrcclin et al. 1984,
`ljrtasun et al. 1981
`Gillis and Kates 1984, Woosley et al. 19E4
`Timmer et al. 1985
`Daneshmend and \X/arnock 1983
`Puozz.o et al. 1987
`Allonen and Zicgler 1981, Greenblatt et al. 1983,
`Klotz and Ziegler 1982, Smith et al. 1984
`Stroshane et al. 1984
`Benet et al. 198,[
`Raaflaub et al. 1984
`Bergstrand et al. 1984
`Butz et al. 1985, f)ahlstrom and Paalz.ow 19713,
`Gourlay et al. 1986, Pond ancl Tbzer 1984, Sau.e 1986
`Olsson et al. 1987
`Mcier 1982
`Benct et al. 1984
`Bressolle and Bres 1985
`Aungst ct al. 1985, Lo et al. 1984
`
`78-90
`20+3
`25 -30
`84+3
`33 48
`
`92
`100
`27 7a
`44
`26+13
`
`9
`34+5
`30
`
`Z
`
`9
`
`

`

`188
`
`Sietsema
`
`Rodents
`
`Dogs
`
`R eferences
`
`Thble 1 . Percent absolute oral bioavailabiliry of drugs, continued
`Primates Man
`20+5
`74 97
`
`Drug
`
`Naltrexonc
`Naproxen
`
`50 92'.r', 68 - 1OO
`
`22 58^
`
`9-34
`
`1o+3b
`
`37
`11+2
`
`79+11
`
`49
`
`7A+ 15
`34
`
`100
`
`74+20
`
`50"
`2+1"
`
`53'
`
`7A'
`
`104"
`
`59"
`
`28-76"
`
`Neostigminc
`
`Nicarclipine
`
`Nifedipine
`
`Niguldipine
`Nipradilol
`Nitrazeptrrr
`Nitrendipinc
`Nitrolurantoin
`Nitrogll'ccrin
`Nomifcnsine
`Norethindronc
`Norfenefrin
`Norfenlluramine
`Nortriptyline
`
`Norzimelidinc
`C)rneprtrzolc
`
`Oxazepatn
`Oxoclipine
`Oxprerolol
`
`Oxvphenbutazone
`Orytctracr cline
`Papar.crinc'
`
`Paracetamol
`I'efloxacin
`Penbutolol
`Pcnicillamine
`
`l'enicillin G
`Penicillin \r
`Pentaceine
`Pcntazocine
`Pentobarbita