C<531'i‘¥i§E«AiWG Eb3:§:ifi§N
`
`BIOPHARMACEUTICAL ASPECTS
`OF ENTESTSNAL DRUG
`ABSORPTIQN
`Prof Freza Fassihi
`
`iary bimad-cf the i'T&ESBi‘fiBTiC circuiaiian and ncfi ‘go include the
`appearance of medrug in zhe 33:5-terni: cireuiation. This‘ dis-
`tinciisn is made because between the gm and the: systemic
`circulaiien. has-the War, the great "iJD‘!sonv trap”.. profecfmg We
`$1.-'s!e'm§c circulation from numerous potential toxins which
`ante? the gastrointesnnal tract‘ Evoiuiianarg experience cf
`environ memai Toxins have pmvided the Iiver sézirh an eyaraz;-r«
`€L33i"rfil‘_‘_,! range of detinxicating mechanisms for namrai toxinfi
`which are active in detoxicating minidrugs. The verypres—
`arms of thee. irap, means that for many drugs. aii ‘mat is ab-
`sxsmed {Seas nut enter the $;*,r$l'erni<: circuiatiun intact. This is
`known as me “firs! pass em-’:;i”. Drugs that shew a substan-
`tiai -first pass effeci ‘n man due to hegzatiii elimination are
`iisiedin "F-abie 1 .
`
`“fable 1 : Drugs ‘showing tear; orai béioavaisaizziiity due in exten-
`sive. firm—pass hepatic slim-inaticm
`Mérca_ptep”urine
`Acetylaaiicyiia acid
`Meihyibheriidate
`Aiprennidl
`Matepmioi
`Amitriptyiine
`Ghécrmethiozele
`Morphifie
`Cs:-umarin
`Naaostigmine
`Nate-cxipine
`Des'ipram.ine
`Nariryptyiine
`Dextr‘q:.>rc:s>axyphena
`Oxyphenbutazone
`Diiéydroergeiamine
`Diitiazem
`Papawfine
`Dopamine
`Pentazccine
`Piéentacelin
`5:F!uorouracia
`Praprancm:
`Giizsceryiirinitrate
`Reserpine
`Hydraiazme
`S9.-ncyiamide
`imipramine
`Serdtxtmin
`isaproterenm
`Testostercme
`Labeioioi
`Trypiephan
`Lignccaine
`Verapamiti
`
`The motility at the smaii intestine tends ‘to optimise cliges--
`técm and absorption. There are primaciiy two iypes ofiniesfinai
`msvement: peristalsis and mixing. Petistaisis determines im
`testing} transit, raie anti theréfare the residence ‘time Ufa drug
`in ihe intesfine. This wiii be most impartant for cczhtrniied #9»
`%éase dosage. forms, enteric casted products as wail as tmse
`drugs which disso.1ve'sI¢_w1y or where afisorpfion is maximal
`aniy in certain ragions of the intestine,» Mixing air ‘segmeniai
`
`253
`
`E N DO_O P_1348761
`
`FACTORS AFFECTING GASTRDENTESTENAL
`ABSDRFTEON
`
`As 3 r'u'ié-, about ?S% of the drag given cgraiigiwili be absorbed
`in cine to three hams. but numerous factcirs can after ‘this,
`some physizfiogical and same to on wiih Iheftsrmulation oi the
`drug. The main factors are:
`1.
`gasirointestinaj motiiiiy
`spianohnic biaud flow
`particie size and drug-dei§va:y‘sy%stem
`
`2 3
`
`.
`
`chemicai factors and drug interacticnsi
`pathaphysiuisgic cuzxdiiimxs.
`
`4 5
`
`After passing th :1:-ugh the pyiaric spitinc1er,'-firug reaches. in
`sequence, -the duadenum. jeiunum and ileum. Thase regians
`have different pH, -digasxive s3nzyme.s"and abscrptive capapi-
`ties. The gelease of food into the cucgdebum causes the
`release of éhniecystokininmancreéiymin and secreiin by
`ztuodenai muccsa, which cause‘: emptying of the gaiitaiadcier,
`secreténn of pancreatic enzymes, and flow (of pancreatic and
`biliary fluid, Bike, which has a {JH of 7,B—8.,8, raisas the pH of
`the dmdenai anti p:3st—duoder:a! intasxina! cements to ap-
`praxknataiy 5-?. Bile saits; w~hi€;—§’3 are surfacaactéve, can pro-
`mate dissoiufion of iipqphiiic drugs and__m.ay aiso increase
`membrane pemieabiiiiy of hydméhabic drug moiecuies
`tbro‘u‘gh_mi<:e!ie forrnafion and sslabéiizaticii.
`it has been
`reamed Ehat bile
`saits
`farm ihscziutvie nonabsorbabie
`compiexes wiih drugs such a neomycin. kanatrrycin and van-
`comycism. Poiyytxeptides such as corticotropin. vasoprassin
`and irxsillin at-3 fiiso rapidtgr degraded by the iritasiinaj en-
`zymes and pirogestercme, testesterdhe =afid aidosteronew are
`simiifiriy unstabie in the intestine Malling, 1980; Meiahder.
`‘:9?& .
`The process of drug abscrpfior: fmm oral formuiations
`irwafsres passage of the drug acmss the gastrsintesiinai
`rtustifisa,
`intm the mesenteric vcircuiaiion
`in the present
`siisxcussiorn, absarption wiii be taken is mean txniy the gmeess
`of passage acress the gastrdintesiinal muccesa info the capit-
`
`P;“bfAFt Fa:-;si‘hz_', D.ep1‘..m' Pharmacy, Iiiemcas Schaol, unziver.
`srrysftne mtwafersranct York Road, Parkfown.
`
`SA Phafifiaceuficai Journat-—Juiy 1 990
`
`Lupin Exh. 1028
`
`

`
`(:é::1“EITi’£_?IN£} E,DUC{g1g>N
`
`Saiufienfi Peilets <2 2 mm iwgrggggigggggina
`L8
`HB
`F
`1.8
`‘fie
`
`%
`
`11
`
`.
`
`*"an g.
`
`P.onao:-aQ
`
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`
`4-.
`
`ouan4-a
`o.
`v.
`ov.
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`u«up.anu
`
`
`o.u.uv
`
`I9
`4.
`an..u.
`
`«-
`
`
`
`
`
`Smalli.ntes.t‘metransitt:ime(h3
`
`
`
`
`
`contractions serve ‘to mix and squeeze the faofi 10 prrsmeia
`sp:'_ead_in§; and c:1niaetwith.:he intestvinai vmi. in adadiiiora, the
`musquiaris mucosa produces {aids in the surface epithetium
`resufiing in an increased surface area and rate of absorption,
`The villi-centraci during this process and resuit in a “mi%king"
`actéen so that lymph fiows from the central Iacieal into the
`{ymphaiic sysiem.
`In maiabsorption states, or in .pa‘t‘zent's wfm imestinai resec-
`ficans absorption 0% some drugs may be impaired fag, digexin,
`thymxine). in patients with gafirointestinai hurry the aizsarzy
`'£i0f‘£ of drugs from stew refease preparaties:-ns may be im—
`paired. in sutjh. cases an akiernafive (eg. effervegcent potas-
`sium salts rather -than a slow reseaz-as preparatéan) should be
`used. Gastro%rr($es!i»nai ioxicity ofdrugs czanbe d%videdinh:> two
`grcups, awarding to severity. The first inciudes {ass serious
`effects such as nausea, vomiting and diarrheea anti second.
`seriauvs afiects such .as,,gastroimestinat erosfitsn, 1;-Seeding and
`uiceraiion Nausea and ‘vomiting are commciniy aaseciated
`with drugs such as pataséium tit:§:3ri<3e_.
`'ami‘n£3;§hyl|ine and
`ferrous sjuiphate. Petasssium chlaride arse causes the more
`$2-rious affects of eroséon and utcaramn, as was aspirin.
`Same. malty administerad drug-s aremore extensixteiy -meiafim
`czfised. in the intestine than in the lisiar. Thus, 'intestEna} .metab-
`ofism may crsnifibute in the uverafl first pass effect. First pass
`effect may so greatly iimit. the bfioabaiiabiifity af e;ra1!y‘a::Iminis—
`fared drugs thai a{temat§ve rs-ate-3 of administration must be
`employed is achieve iherapeuficaiiy ef§.emive biead Eeveis.
`Examples of mucc:3'aE'metab1:sfEsm of some drugs. are Shawn
`in Tab§e'2 (Ritschel 198.6).
`
`‘E“ab'2a‘2: Examgxes cf 8-come drugs for which gastroiniteatiraai
`metaboiism apply
`
`Acsaiwsaiicyiic acid
`Aidesie rune
`P-AmԤ.mt:anzoic: acid
`P~Amir:c:h'i;3puric acid
`Chlorprmnazine
`Cbnazepam
`Corfisone
`Hydrowfiisane
`Meperidine
`
`Methadcxne
`an-Methyédapa
`Peniaztaairée
`Progesierone
`Stiihestrol
`SnEonamides
`Terbutaline
`
`Natev: The drug meiaboiisiag enzymes normaiiy assaciateé
`with hapatic tissue have an been iaund if: tha iniestinai
`mucosa sf ammais and -man iflatftiaia, 1973;‘ Thus the syn»
`thatic reactions (oxidation, reductions and hydrolysis) as wen
`as the conjugation reactions rrormaliyv associated with deh:)x§~
`catian are as’ catalysed» by gm enzymes fieg, Gym-chrame
`P-450, aioohot ciehycétogenase, MAO} {Inga ciecarkmxyiase.
`reductases. esterasas, arnidases, acetyiase. sulphokinases,
`glucuronyi transferases and amino acid conjugates»). The
`lower gut also hafbaurs intesiinai microofganisms éhat are
`Capable ofmanax bintransfcsrrnafiori reactions.
`The mean transit time 13:’ unabsorbed fond resa'dues or in«
`soluble. grannies, paeéiets, Earge unirdosage fmms and 50%-
`utions through the human smafl intestine is remarkabiy con-
`.sfe'm’c and "is estimated-tarbe about 4 hr, Figure 1 {Davis e? as;
`19.8%}. ‘fhe resufts eif’ severe} investigations hava revealed
`>2?‘-fiat this ifitasiinak traifrsii time in 'h’ea.£$h}:. subjects is not in
`ffuencad by the presence raf faod. «exercise and densiiy of the;
`mzateriais. it appears mat physioiagicat discrimmaiizm sf meat:
`semis and liquids takes. mace infihe stcmach ratherihan the
`smafl be:-we!. However,
`intestin‘a¥' transit rate is decreased
`where there is a Teduciiart in digestive iuice secrefian and ’(h:.*«
`refine secretion, and is increased with diajrmneai cenditmns
`and during énsufin hyipogtycaemia. Drugs whose abscnrptian
`can be delayed, decreased er enhanced why‘: taken with
`P118815 are Eisted in Tame 33 and 4, respectively.
`
`260
`
`"'~nrv‘:~:--'n..auIz*-1r‘r2
`
`'5
`
`4
`
`6
`
`6
`
`3
`
`-..
`
`Number of subjects
`
`Figure 1: Range cf individuai data. points etxsamed in
`subjecis studied "far intestinanransit time cf pharmaceuiical
`damage forms according to feeding condiflans using gamma
`scintégraphy
`Kasai: F -— fasted; LB ~» fight brea!-zfasé (1 500 ml} ; -HB—— ‘heavy
`bzeakfast gage 3-:3
`A
`(F3543 mwdi ' dfram aws errai, mash}.
`
`Tabse 3.: Drugs whnse. absorption can be deiayad {Group I} 4::
`decreased ‘(Grants 11} by feed sr nutrients
`
`
`
` Group 1* Group II*
`
`Amépicimn
`Penicikiinsfe. VH3
`Tetracycfines
`Antipyrifiev
`iseniazid
`Chiarpromazide
`Capmprif
`Levociiapa
`.Fiifampic:ir:
`Lincsmycin
`Proguantheiine
`
`Acetaminophen
`Ampiciilm
`Amoxicifiin
`Aspirin
`Aiciuéenac
`Cepfiaiaspsfins
`Gimeticiine
`Digoxin
`F’urose_mide
`lndo;1'ro'fen
`Potassium
`Metrcmidazofe
`Pirexicam
`Sifitenamides
`Valproic acid
`Quinidine
`
`*T?:e eifecfs ofrhese drugs ml? bra enhancer! when taken on an empty
`stcrnach
`
`Note: There -are.c»:mfi‘sc’:inQ reports concerning .abso:'ption gf
`drugs in the presermaiand absance :23‘ food and it is {iiiffi-?;uIt“xrD
`generazize, from the infzzrmation given abmra. Hswevec,
`detayed absorption in this coniexi means amt drug ::i'oax:a?%-
`abifity is net affected but me onset sf action is deéayed. Ge-
`craased absorptian means» ihat drug h't0auaf'abi}ity- is af-
`faded.
`
`Tabie 4: Urugsztcz be taken with-meats
`Acatyl-leucine
`Metfarmin
`Aseiylsalicylic acid:
`Methysergidaé
`Aiciofenac
`Metiazi niic acid
`Aiiopurinof
`Matoprzfloi
`Amicsdarone
`Mexranidazale
`
`SA Tydsmt *.x§rApteeb:wese--—dulée 199:3
`
`
`
`ENDO_OP__1348762
`
`

`
`
`
`CCiNTINl}1l$:G.EI)UcATI(JN
`
`ii?‘
`Haciruia 5~.:miuosalicy;:lic acid
`
`COG“
`
`9.:-:\dl$3i
`
`_
`
`i CmcinicM...
`I-xnawro bic
`
`A231:-mpazene
`Baciofen
`Berixbrcamsrnne
`Benziodamne
`Bmmocri piine
`-Qariiamazepine
`Ghlofai hydrate
`Cinnarizine
`Co—trimo>:azoie
`Ciiazgpam
`Diclofenac sodium
`Dicoumaml
`Diitalene
`Discipyramide
`Eihambulol
`Flavaxaie
`Giibencamide
`Glibarrruride
`Glicazicle
`Giipizlde
`Griseoiulvin
`Hydzralazine
`i-iydrcschiorethiaziije
`lbu prolen
`indemelhacin
`Eran salts
`lsexsurpine
`Label»:-lol
`Lavodopa
`Licleflazine
`Lithium clfrate
`
`Minocyiclitte
`Nalidixic acid
`Naproxen
`Nlcoiihiii acid -l- defivatives
`i.\';’ifii;i rink: acid
`iiiiiu r:9i'néai
`l\3ltroillréaii’icin
`Oxyphénbulazbné
`Panéréalin
`Pheynlbulaztrne
`Phenytoin
`Pivaiiépirsillln
`Potassium salis
`Pmp»ra'n0|ol
`Reserpine
`Flltaailavine
`Spiionslactone
`Suiindaz:
`Su'lpihlrl_pyrazi3ne
`Theophyliine :4 derivatives
`Tinidazole
`Tclazamide
`Toibutamide
`Tdlmeiin sadium
`Triamterene
`Vaiprfiaié stadium
`8~ Meihoxsalen
`5~FiLlrc>ura'c'il
`
`Nata: ihe effects ai these drugs will be enhanceii when taken
`with meals.
`
`TF\‘13iNSiT KND DR UG ABSOFE F‘Ti0N ill! THE COLOR
`
`The distal portion of the gastrointestinal tracl, the colon, has
`as its primary iunciion wallet and electrolyte absorptican (prox-
`ima hall} and the storage cf faeczal matter print in its being
`exiiselled {dlslal half). Qrug .abs»::r;3ti{5n from lime colon is likely
`in be quite slow in comparlsan with iiie small Ernestine tile’-
`cabse of the small surface area available for absorptien.
`Patients who take nc-n'—steroidaii
`.anii~inflammatory drugs
`have an increased incidence of gasiric biaeding and peptic
`ulceration. Thus cases have been reported in which incleme-
`ihagin delivered in an osmotic pump was associated with in-
`teatinai perforation. Single unit dosage forms can be hréid for
`long periods {442 h) at the iiencaecal ‘salve before moving
`inta the cQlcm..»Coi<::n ccvritents are nriapelled-»down the‘ tract by
`a “mass movement", which is similar to ine‘ sgegmenting can-
`tractions seer‘: in the smali intestine, and D('fi3l_.i!'S>Cll"lly several
`times a day. The greatest proizccsriidh of lime in tile (5! .irac‘l is
`spent by the residues of a meal moving through the ccllcm. in
`diarrhoea the rate of rrtcmemenl. through the Colon is fast and
`fluid absorption is incomplete. The ideal delivery syslem to
`the maximal GOIDH should retain the drug within me system
`far approximately 5-8 hours» after administration to the
`paiient. to allow this fair gastric emptying and lransit Waugh’
`the small
`iniesiine and shcuid then disperse and travel
`thmugh the ascending Golan. Oraipreparaiions which are re-
`leased in the salon wcuic!’ has of particular lzalue in {he mean»
`agameni of patients with inflammatory bowel disease-where
`the taping! action of a drug may be cf ‘additional value. Sul-
`pha:-:-alazine isalaxopyfin} is {he mi:st‘effes:t%'ire agent in main-
`tain remission in ulcerative cclitis. its use is limited by adverse»
`reactions including allergy, intolgrence and male. infertility.
`Sillphasalazine ccnsisis oi two compounds, sulphapyridine
`and Syamino salicylic acid (S-ASA) joined by an azca bond
`which is spiitby azo-recluclaéeé: fmrn eolanis baeieria, releas-
`ing the constituents (seé ‘Figure 2).
`
`SAPhan‘nac:euzical’Jcu:nal«~«July 1996
`
`Figure 2: Si‘l.e«’speciflc: drug delivery through Selective pro-
`drug biaactlaxaiion at the target by azaweduclases of anaer-
`obic colonic» baclear-la
`
`Re-‘cent swdies have shown that S—ASA is the active com-
`ponent whiciw both‘ heals and may reduce the number of re-
`iapises in ccxlitis. Sulphapyridine appears to act as the carrier
`rnolecuie far 5-ASA and is iileely in be responsible for most 01‘
`the side effects and allergic reactions-. E3—ASA cannat be sim»
`ply give-nvorally lathe treatment of eoliiis because ii is unsig-
`ble in acid and is also‘; a-bsorbevd by the small intestine and will
`rioi raa ch iis target (the colon)" in eéfective concvemlralien. Oral
`preparations intended to deliver compounds to the human
`colon have been developed as coated capsules corilaining 5-
`ASA and a prodrug form of S‘AS;\ inmiving twis melecules at
`5«ASA linked together with an an band which would be splil
`by bacteria in a similar way lo sulphasala2ine.. A .specific en-
`teric scaled tablet ccmiaining 5—ASA in pellelssmbedded in a
`dis-pelrsible matrix system seems a possihlility for the man-
`agemeril of ulceraiive colitis. Other drugs that are most Elks-ly
`is be presented to lhe calm for tapical release and al:isc:+rp—
`licln are saliaylazobenzciic acid and steroids $1.-sch as premi-
`selone phosphate‘
`
`BiOPHAR !liiA$EUTlCAL iMi3Li{3ATiC}NS EN RELfi['l"lON Y0
`PATHOP1-?¥SK)LGGlCAL CHANGES IN
`
`{EASTR01NTESTINAL DISELAS E
`The pharmaceulicai formulation of the drug substances can
`affect Elie blcsavailabiiiiy oi the drug; We knew how the phar-
`manoidmtic and pharmacadynamic pracassses determine ine
`conceniralions of the drugover a period of time at the active
`site and new pharmacological effectoccurs, New we must an‘:-
`amine how these pmcesses iriieracl with the pmcesses
`underlying the peinfology at
`the disease allowing usaiul
`raiionaiisaiian and interpretation x:sf’dr~ug action».
`Sieatcrrhaea is a izondiimn in w‘hich!l1ere.l3 an increase in
`faecal la! excl-alien as mated in pancreatic dise-ass and occurs
`in gastrintestinai disorders such as caeliac and Crohrfs dis-
`ease, small bowel diverticulosls. vagoiclmy, intestinal reseE~
`lion am} after ingestion of neemycin and choiestyramine.
`‘Subtotal or total villous atrophy may follow chronic‘ treatment
`with p-aminosalicylii: acid, cytotoxic drugs‘, celchiljine, par-
`amomjgcln, mefiormin and siow release putassium chlczfide.
`Villous atrophypccsurs in coeiiac disease and demlaiitis her-
`patifo1'r'mis.Cc:eli:: disease is ihaughl in be caused by sensitiv-
`ity lo cereals and food ccanialning gluten and (alien presents
`as a malabsorption syndre-me. Anaiher fastor influeniiing
`drug absorptlan in coeliac disease might be an increase intha
`pH of thagut lumen or acid miicrociimaté. This mighi 'cor}irib-
`ute to more rapid absorption of basic drugs, such as ;:aropra+
`nelsl. Sn the other hand the abscerptlon of praciz:-ital i3 delayeci
`in caeliac disease. The abscrpiiczn of italic acid is pH de~
`pe;’_a_1de“nl and might, tiierelssieé, be inlfuehced by changes in
`acid .micrsclimaie in patients with coeiiac disease. Ii is poss-
`ible that the permeability of the intestinal mucosa to drugs
`might be situated by disease, but liiiie information is available
`an this point.
`in Crohrré disease there may be -extensive ihi'cl<ening of
`thé gut wall, narréewing of the liimen and saimndaiy changes
`
`26'!
`
`ENDO_OP_1348763
`
`
`
`

`
`
`
`DRUG USE
`
`{A 1&3? Updait:':)
`
`A Guide Far T12:3 Héairhv Praféssiaflszf
`
`This reference work is new availahlla in its St}: §:3;<2itia:>;“1. Easy to use, reiiéhle and prixcéicai if
`sheuéd farm -a part of the‘wf::rence;s'nscd bythe. phanhaifist-6:1 awn-tine daily basis.
`
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`Jzkfiza vfzée sozxerasgé :32‘°!1ée-fcarz; iz':z:r ékéswzle fir.-zwz afbrlntkffiéfgprojécfi
`
`Ffzgre .33’ as P£?.'.j5’ rear! saeséféwr gaad rma§;r~rejfere;zce xgmvfér drug zz_mj;;vzr.s1e: daizfa» .:i;:‘E=-sr 5112 ma:*;;vaF'e';_.v
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`zzé}rz.s*a*i2zre€:z’?2§ sass}: i1a5?£:§aflafxvfiouféezsxirt;9?:rI££$‘§9é’t:V.
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`
`5z‘:;ce.=. Ike. {$51 ediszbzz {I985}, mverafnew sinpasriantpismrméxsaiagiarzf‘ azzmrés flaw zzpgiafarea’ an
`2‘??? 5z9‘I¢.z$'§ Afkbéxz fiwfkat. }'?ic?.s’u1?I #311? 4638?? M:'2ic.»r;*é;a?arb*:ék! £11 mgr zigzdirfé; Cfiapézr 3&5" figs been
`e?.r§erm?’-’:.i" fit’ zI=*ze:‘Im$'.«,.* variant tésfifay afcfrug avmpariszanx krgfziafi 1'[E33ma:)1 ére 0fzm?~!0 a'!§£pr::*Sc.r1'-
`:53:/3?&7&‘4§:prfl:7!tI1bH€r.
`Z—”!:::-52 xkzwfizée at £s:).?:3;*&rz3"£>:'1 sftéégragéerrzktv effis .er.‘r".;:;9ca§'&? ar:I!.€‘.<3’e§z72=:?5*-
`.ag§*;-‘:*.m:s; 1;‘/ie::o:&£.«;vz&;é :1'z2?2;;?.:x:2§'éE«.*,£*;r.s?,. z§;‘:'2;2e' ibwernkzg cage»-zerr mm’ §er:zea¥::2ep:@se5* Tée .r.ec=
`1:29»-:1 :.wg.erIk!—!?*fcTd’rwg &3’.§é";*3'efi57 érearz remzskzérz.
`fC?E ?34£§;%»!ZJ£€?
`
`2"u'é'ai}éib3e’from:
`
`33}3}mT3_?)"H0use
`2$3utf= fitreeri,
`Briiaxnfenteinv
`
`_
`‘Ike Beak D::g:&a'rt1:i1eI§¢1
`Thin P‘i1armaceutica.1 fiacéeity efsoutb Africa
`Po Bax 31350
`Tel: (e11T).339-1752
`Braamfcanteir;
`Fax: {G11} ‘4{}3-1399
`2317
`
`
`
`
`
`ENDO_OP_1348764
`
`

`
`CUNTINUING EDLICATIQN
`
`cause» body siores are considerahie, and partly because
`few disoriciers cau$a -Bi; afisarptisn in faii beimsr ihe daiiy
`requiraments. Protein maiabsorptiori may read to hy3;«o~
`pmteinemic oedema, uauaiiy an‘ the icgiwer iimbs. Gaby-
`dration, potassium ioss and muscie weakness can follow
`prefuse diarrhoea; Gaicium deficiency is'ci:2rnmi3n and is
`due pariiy‘ to Vitamin K3 deficiency with impairem a¥:&$Gt;)~
`firm and pariiy :9 caicium binding with unabsomed fatty
`acids-_ This may cause bone pain and faiahy, infantile
`rickets where esieomaiacia may scour in severe aciujt
`coeiiac disease. Thiamine deiisiency {Vitamin 8.1) may
`cause parestheséa and maiabsorptiors of the mainly fat
`soluble. Vitamin Kean head to hypap-rothrnmhinemia with
`bruising and bieedirig tendency (Merck Manna! 1987}.
`Severe rituaflavin {Vitamin B2} deficiency may cause a
`safe tongueand wguiar smmaiitis, bm Viiarrjn A, C3 and
`niacin daiicienciessaidum Cause iziériicai pmbiems.
`
`.3. Man,ifesiaiii5n.s of ma'1a«i:ss.i:-rption due to an underi;-r’ing
`disease: same diseases that cause maiabsarpiicrz. have
`ciistinisiiy ciifferentnlinicai preseni:aIion._ eg, ihejagzinciice
`cf biliary cirrhasis and pancreaaia carcinoma, the abdo-
`minai angina oi mesenieric ischaemia, the baring centre!
`ahdc;-minai pain ci C5’!i‘{}.E‘:i'G pancreaiitis. and the severe,
`persistent‘ uicar dyspegsia -of the .Z<;'}iinger«Ei_iis»3n syn-
`drome (syndrcrme caused by.a_.gastrin«s‘ecre€ing;
`tumour
`of me pancreas. ;:.mdu::;i:3g a high concentration at hy-
`drochioric acid in the stomach-: ulcers are farmed in the
`oesephagus-andupperiniesiinaiiraci).
`
`:1.
`
`Sympwms associated wizh the ageing processfieideriy}:
`Stmctu-ra-i and iunct-ianai changes in aha gastrcziniestinai
`iraci _have garficuiar significance: on ihe éifiectixzaeness sf
`r:-rally administered medicines. Gastric ‘acid output and
`peristaiiic activity decrease with age. The resuii: is a reta-
`Iixrerg high iriaidenrze of anaemia .ris<:essita2ing supple-
`mentary iricrganic ircn therapy, which can form newsh-
`sorhabie iron c<:«rr}plexes’w~'ith tetracycimes and sgrntixertic
`peniciiiins ii‘ admin-isiereci conuurrentiy. Siowed gs-.”sir§<":
`muscular aciiviiy, decreased emptying time ‘and the
`rising (ii the pH oigasiric juices may irr¢r'easa'tir:e,irritat~
`Eng effiétt sf somedrmgssuch as aspirin or phenyiain, be»-
`‘cause cii th’eii'e’:(irended .tirne~in the stomach.
`
`
`
`Tabie 5: Maiabssarpticsn fine in disease states resu hing {mm
`impaired digestion
`
`‘ I
`
`mpaired digestioh
`resuiting mam
`
`Conditions
`
`inadéquate mixing
`
`Gasiroerzierostomy
`Biifrmh .iE.i;asiro~eciomy
`Gastrrzcolic fistula
`
`insufficient digestive
`agents
`
`improper miiieu
`
`Chronic pancreat-iiis
`»Gystic fibrasis
`Chranic éiver iaiiure
`Biliary absiruciiim
`Riaciasia
`Sucrasisdsoniaitase deficiency
`
`Zoliiinger-Eiiiisonsyn{§rcm1e.ii0w
`ducderzaii pi-i}
`Bacteria? evergrowth-biind maps
`iderzonhlgaiion sf biie salisj
`Diverticu Ia
`
`'
`
`-263’
`
`ENDO_OP_1348765
`
`in matiiiiy. The effects on cirug absorption are variabie and
`unexjaiained. The abficrption at rifampicin is unaltered, that of
`ciindamyciri and suiimamethoxaznie is apparentiy increased,
`while the absorpfion oferythrornysin-staarateis reduced.
`in smaié bowei iiiverticuiesis, which is we at the most im-
`panant pat-iwphysioingiizzai candiiions in which there is a shiii
`in ‘gm iiciza in Va preriominamiy anaerabic popuiaiiiran which
`may be respesibie fer sieaiarrhoea arifi maiaizaorptien, Ai-
`though in such circumstances increased meiabviism cf drugs
`by intestinal bacteria might be expected, absorption does not
`seem to be decreased.
`A
`Exampies of ciinicaiiy importani changes in drug 3bS{:ar;3-
`{ion in paiiafits with gasiroiniesrinai disease are as ioilowsz
`deiayed gastric empryinghas baen shown ta be responsible
`for merapautic faiiure cf ievodopa in patients with Parkinsorfs
`disease. Achierhyflria {absence of hydroehimia. acid) czccurs
`in pemiciaus anaemia and is;c:am2wr.'in in the eideriy. The re—
`suiting changes in pH wiii infiuence cimg ciissoiution and
`pisssiiziiy gastric emptying rates and so after the absorption of
`many drugs. Variable affects cf 3.-ug absorpiian have been
`repcrteci after gastric surgery, Hgpoihyreidism faiiing is re~
`srsand to arai "t§"iyrCsXi.r‘t9 0'r’ir§iGd0’£h3rmnine is ariimportant but
`rare compiication of caoeiiac .di1aeas»a. The ri5i<: of cznkimcnaiezv
`zoia induces? apiastir; anaemia is g—reatiy increased in ifiatienis
`with coaiiacdisease and foiaie riiepietiari and cst_e;omaiaci_a,is
`an imporzant risk with prolonged anzi—c::m‘ruisant theramr in
`ccietiac: disease. The deiayed .absorption of many drugs in this
`conditinn is uniikeiy to be oi.therapeuiic significance.
`Eiiarrheea, with accelerated remark intesiiriai transit may
`have important effects can drug absorprirun, pariicuiariy with
`the siowiy iii-ssciiving or stew reiease _pr9;;3araii,onsi
`iruzieed,
`diarrhoea has been >hi8ԤCi reszicniaiizie for failure of orai contra-
`cepiittzn.
`
`MA%.AE5G'RP'T!QN DUE TO STRWCTU HAL AND
`FUNCWGNAL C-I-{Afr-1G ES
`
`Many difisrant iciiseasas or their consequences Cat‘: cause
`maiabsorpiitan eiiher by means oi impaired ziigestiarr {Tahie
`5}, nrimpaired absibrpfion, {Tabie.,6}.,
`
`Signs and symptams associated with malabsarption
`
`>1. Manifestations directly attributabie to maiabsarptien:
`weight loss, gicssitis, aazpopadai, spasm, absent iendcin
`reflexes, wt-aneous bruising, abziaminai distensirjn, fiat»
`uienca, gbdominai bieaiing and disscimiort due to in-
`creased buik cf intesiinai »c<miems and gas productirsn.
`flermatiiis herpaiiforrais isciien associated with a miio
`degree of z:eeiiac—iii<e enieropaihy. Diarrheea is not ai—
`ways present; Sometimes siieatorrhoea accurs —— pate,
`sfflfi, buikgi, maiodcifaus .Sto0‘is,Miriai siicicrio the side of ihe
`ioiiai how}, er float and are tfiffirsuii 1:3 iitish away. This
`kind sf 3190!‘ is most iiiazeiy to occur in coeiiac disease or
`trosicai sprue. The stools in chronic pancreatic disease
`may appear grezasy with frag ilcatirag gicibuies of fundi-
`gested dietary fat ifrigiycerides} because of pancreatic
`lipase deficiency (Merck Manual 198?}, Steaierrhoea
`can be '§)}TESEi"£f wizhsut fisrici abnormalities at this stz:-oi.
`Expiosive diarmaea with .abdominai biciating arid gas af-
`ter miii: ingestion paints in iactasa i:Iei_ic;ienoy (aiactasia).
`These effects are seen more in the eideriy and [marma-
`€§§5i’i‘!1¢Iit1i€0!‘ii“i}§
`csi‘ drug "therapy can piayan important roie
`in opfimising drug use inihe eéderiy.
`
`2.
`
`liiiartifesiazicins céueto deficiencies secendary to maiab-
`sormion: the range and severity cf nuiritianai deficiency
`resales to the s'e‘sréri%~yr of “the ‘primary diseasa and me
`eras of the GI tract vinvoiveci. Many patients with maEab—
`sorgation are anaemic, usuaiiy due to deficiencies of iron
`(mérsrocyiic anaemia) and ioiicacici fimegaiobiasiic ahea-
`mia}. Vitamin B12 ‘deficiency’ is‘ unsomman, partly be-
`
`SA Pharmaceutical Journai -- Jmy 3 990
`
`
`
`

`
`CQ§}:l§}§NGiEfi1l(ZiATIQN‘
`
`solves so rapidly that most is in snlulion before mucli has "en-
`tered. the .irlte$iine,__geelric emptying Iclearly influences the
`raise all drug absarpiian. Hasiening gasirlc empmng, for'e>z—
`ample, qulckefis émg ab3i3i'l‘.Di‘i‘0rl from eeluzltm: some drugs
`do not disslxzlilse in the stomach, whereas‘. inme iniesline both
`rapidly clissnive and pass across the §i5ileslina-l- wall. C-‘:'a~3ll'li':
`empiying; iben tlréimatlcailgs alfestlzi {fie lime and gaerhaps the
`rale of clrug iabsorptien. An‘ enieric mated pmclucl is an" ex-
`treme example of this situaiien. On‘ the eihe‘r hand, same
`drugs such‘ as grlseoi-ulvln, lhai is sparingly’ soluble in bolh
`gastric and ln?es*il;é‘a.l fluids, these may already be lnSUfii{:ie‘nl
`lime fer d%ssalui§en and absohpllan when this drug is-aclmlnlésw»
`iered as a _scd:'d. with a fixed Sl"l£':l:‘l'tii‘n«'e within me email inies~
`tine. the _aili>‘w release of iauch adriug {mm ‘the stomach in.-
`creases ihe total time if is in the intestine and decreases the
`ccncentratim at any one site. Eésili conditions femur in;
`creamed beioavailability. As mentioned, feed,_ la: in parficular;
`delays gastric enipiying, anal ililsijelay may be one 35% the ex»
`planallons" for the’obse'n/em‘ increase in me "blo3vallabilE13; 0%
`gfiseefubiirl when ‘taken with _a
`laity’ meal.
`it appevars that
`'pl1§,rsic»lt:g’ical éllscriminatiiéri 1'cvl‘m'ea’l solids and liquids takes
`place in the stomach rather ihan the email bcxwei. Small ln'tes=
`line transit lime ‘zstremarkainly c0nslaI%t.irrespacllxre ei size or
`the dosa§e‘fo?m,- densiiyor presence cal iced, Single unit do-
`sage terms‘ may be held for lC}Tl13.. periods a! the ilaocaecral
`vaiye bemre entering the salon. Trar_1s.it time of dosage l‘_c;;-ms
`is shorter when fibre-centaining food is cansumed, as dietary
`fibres affect the digesiion process. Subsequently as the in»
`tesilnal fluid .and contenls move late tllelarge .lnl§2sii'ne and
`water is reabseit-edl the resulting. compaiziinn :21 the solid
`conienls may severely limit funliar zfisscziution and hence atw
`30 rptlan tn’ idreg.
`Chemical factors afieetlng drug abSUf;iflDE_<3G 5:3 by lumi-
`enclng the slate €)l":lie»: drug in the §f'l‘i9:5°£'lll'E. Thus tetracycline
`antibiotics lslnfcil sirangly tevcalcium inn and .cel»:;iun:: rich food,
`fiespfldfsiailgg niilk) prexréfits their abs:-rpticnv. Sémllariy. the use
`ml’ liquid palafiln as a iaxatlsse will retard the abS<24€'pfi£3fi oi lipe-‘
`.p%lillc.eubst-ances. suxsh as Viiamirl‘ K.
`
`Greg‘ abscirpiion in paiierile will’: gasiminiesiinal cfiseese is
`‘variable and unpradicialjlxe. This varlailen is uftezfi pearly cm-
`relaied with the site and severity" of diseasaxchemiizal strun-
`ture» al-"id-C}'lQ_miC8l pmpenies of :3he"d'mg_ s’:udiecl. Overall. the
`clinical si_gm'ficansa at abnnrmal drug ebscrpiion is unknown.
`hutlhere l_1eve»i3een oc§¢aelaénal.lreports el iherapeuiia failure
`attributed to ihis‘ca’l.:4se {Table 71.
`
`Table 7: changes in blood le#e.ls of some drugs attributed to
`Gaelic; or Groizn s Disease.
`
`Disease V nrugs siieiixihg‘
`cmiditian incfeasers
`-bicodlevels
`
` V
`
`Drugs skewing
`dadreasea
`bluodwltels.
`
`Cuelie
`disease
`
`Aspirin
`‘C_e‘;rhalexin,
`E_r§£tfir0lTIyCifi’Sleafal_e'
`Fusidiclacld
`Pmpranelel
`Suliameilioxazule
`
`Anelaminophen
`Dlg::>xin-
`Pi*~zam:J.lc‘illifl
`Praclolclll
`
`Crohifs
`disease
`
`Ciimrlamycirl
`Sediumfvsidaze
`Suifatnelhaxazole.
`
`Aceiaminaplien
`Cegihalekin‘
`vfiiryihmmylcin stearate
`_l.inton‘ly't2in
`Trimethrsprim
`
`Sfl:Tydskr§f.vi:ApteeKwese~Julie 1.998
`
`ENDO_OP_1348766
`
`Table 8‘: Maleb$0r;§iién asseciateij with lmgtxalred pl’!ySl0l(}gi~
`cal cenditions
`
`' E
`
`condiiiet-ls
`mpaiiedahsorbtlorl
`resulting from
`
`Acute abnermal
`egilheliurh
`
`Cl‘l:‘rc~nic‘ abnormal
`epithieliu'm
`
`Short bowel
`
`Acute inieslinal infecticné
`Neemycln
`Aicolwel
`
`Coeliaceisease
`Tropical sprue
`Wiilppleét disease
`Amylcéd
`lsthaernia
`Crohn’s disease
`
`lrfiestlhai resectlcln lor“{3rohn’s
`disease
`*v’:3lvulu‘s
`IniU3SUSi§8Dil{>l"l
`lnfarclinnv
`
`lmpalrecl iranspori
`
`Blocked leafs-als— lymphoma.
`Lymphangiec-tasia
`Addlsorrs disease N? iranspori
`enzyme
`? Abeiallpapmleihemia
`
`
`Modified from The Merck fielaeual 15;? ea’ {$987)
`
`Changes in me-lesion during ageing cause cnnsllpaiizzon,
`one in‘
`lime more lrcrublesome funcslonal pmblerns cf the
`elderly. The result may be overuse all iaxaalivee, which can
`lead in dehyizlratlcrz, hypekalaemla and reduced absorptlen of
`fafisoluble vitamins. Qohsllpeting drugs, such as certain arr
`taclds, antlhakpartansives; anlidlielineraglce, aratideplfessanls
`and ‘me phenothiezinesi must, therefore, be used wié-h care in
`the elderly.
`it aepeare that drugs which are ainsarbed’ by
`in general.
`specific transperi pmceseas are l’l'1<’.‘xl"é
`lil-iely to be affeefed
`than those iha1"are'abscrbed by passive difiuslan. The ab-
`sorption by active transport of galactose, calcium, thiamine
`am: iman la reduced in the’ elderly, winesteae studies of ease:
`rzetamol,
`~as;:niriri, phenylbutazenje and sulphainethizole
`demonstrated normal absergoiicrn oi‘ these passively absorbed
`drugs in the elderly,
`CONCLUSION
`
`with wider appieclaficn of pharmacnklnetlc and -pliarmacady
`riamic; principles and ma intieszlucrtien of therapeutic drug
`monitoring. a variety? i>E'c'ontro‘llenl release’ ma: dasage forms
`has been introduced over the last decade. Coniretled cm»
`slant drug input mlghi prmxide greater‘ seleefivlty of drug ac:«
`‘lien and reduced toxicity by avoiding» ihe successien of peaks
`.and troughs of drug concentration associated with con-
`lxemienal therapy. Drug absorplien from many of these do»
`sage forrns depends er’/{he location elihe delivery system in
`the gaslrairlleslinal tract. }ndividl1al’difierence.s in the exterit
`eel awbsorpiiori have pharmacoklnelld’ ctiizsequences,--similar to
`lhose arisliig from -changes in
`form iorrnuiafiong
`Asihe meuih ta anus transii time is typically 1 ti.) 2‘ days,
`ihese data an gastric and small intestinal transit" ‘limes indi‘-
`cale that, for the m.aloriity elihls time, lngeslecl sczlids age in
`eiiiier the large bowel or the rectum. Wilh ihe ;:rh3ssie¥'ogi:
`iniermaiion given. the poe‘s‘il:éte rale arf gastric emptying and
`intestinal transit in the absorption‘ of drugs glven in ‘mild
`dosage" farms ce_.n~ be understand. C-ansidezingi tlial malny
`corwenticnal tablets and capsules, in which the drug »:lis—
`
`‘
`
`284
`
`
`
`

`
`C(§NTINUINGbEDUCAYiGN
`
`To summarise, aviarge number of faciizsrs can -influence
`
`systems. drug form. excipients, cirug amount, administrafian
`scheduie, route of administration. physiological factors, such
`as age. sex, body weight. ganatic, nutritional state, disease,
`pregnancy, gut flora, gasiroiniesvtinai ma-iiiity, renaifunetisn.
`physicai aciivitg: and dieiary facmrs are also important and
`they may Inqreasediug ..E.bSOFpi!O_hQt:33"feC1£?fug metabolism.
`drug excretion. drug receptor; site znteractsans and finafly,
`marmaccaiogica! factors can affecfdrug absorption. Effect of
`::f::; :21:
`iary flow, local brood flow. urinary pH. tdierance and envirorv
`memal
`factars. are an 'im;:or2am determinants of drug
`aijggrpfign and response,
`
`REFERENCES
`1. Davis 83, Hardy JG and Fara JW (198%): Trarjsit of
`plharrnaczeuticaifldasage farms through the smafi m*tes-
`me’~GUt' 27:‘38‘°‘8g2
`»
`2. Hartiaia K (‘i§i?3): Metaboiisrn of. hormones. drugs and
`ether‘ subs