Page 1 of 22
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`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`PhannocolO9Y S/ e
`Rang
`
`CHURCHIllllVING5TONE
`An imp',nl 01 Else",ier
`
`@ 2003, E I ~vier Science tim.led .
`
`No pat1 01 this publication may be ,eproduced. $k)~ed in 0 retrievol
`5~rem . or tlan~mi"ed In any f()(m or by Cloy meo"5. ~echonic .
`me<honical, photocopying, recoroing 0.-
`e>'h...""'fW,~e . ....·'hour fhe p·;or
`permlui()('l of the publishers.
`
`Previous editions 1987. 1991, 1995, 1999,2003
`
`Oiginol ISBN 0<143 071.45A
`
`First Printed :n Indio 2005
`
`InOion Rep"n, Isar'.! : B 1-81 <17-917.3
`
`This edilion j~ fOI sole in Bangladesh. Bhulon, Ind.o. Mold ive).. Nepal.
`Pohston, $n lanka and designoled coun llies In Soulh-EosJ Asio Ih(009 h
`Elsev~( (Singopore) Pte. ltd Sole and pt.fchose 01 Ih is book oul~ide of
`rhele :oun t"e~ ;, unouthrl!.ed by 'he publisher
`
`Notice
`Medicol kno......ledge Ii (OnSlon l'y chong.ng Srondord iofety precaution .
`must be 10110we-O, b... t o~ new (eseo{ch and cI;n;col elC:perience bloooen
`Ovf knowledge, chonge~ In treotmenr ond drug Iherapy moy bec o'T'le
`necel$Ory or oppropriole. Reoders ore odVised to checl the mosl Curre:nl
`product in/ormotlon provided by the monu{o<:lurer af ~och drug 10 be
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`Page 2 of 22
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`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`Contents
`
`
`m
`
`()
`
`
`'"
`5
`z
`GENERAL PRINCIPLES
`1. What is pharmacology? 2
`
`Phormocology in Ihe 20lh cenlury
`
`3
`
`
`2. How drugs oct: general principles 7
`
`The bind ing of drug moiecule, 10 cell s
`Delensilisolion and IQcnypnyloxis 19
`
`
`7
`
`
`3. How drugs oct. moleculor ospe<ts 22
`
`Torgels for drug oclion
`22
`
`Rece plor prole Ins
`26
`
`Ion channels. as drug lorgets 45
`
`Control of receptor expression 47
`
`Receptors and disease 48
`
`
`... Cellular mechanisms: excitation, contraction and
`
`se<rehon 51
`
`RegulohOi'l 01 intracellulo r calcium leve,ls
`Exci tation 55
`
`62
`
`Musc.:le controc/jon
`Release of ::nemical med iators 6 4
`
`Epilheliol ion lron'pOr! 66
`
`
`5 I
`
`
`5. Cellular mechanisms: cell proliferation and
`
`opaplcsis 69
`
`Cell proliforo lion 69
`
`7 d
`
`Angiogenesis
`Apoplosis ond cell re movol 74
`
`POlhophysiologicol implications 77
`
`Therapeutic implications 77
`
`
`6. Method and measurement in pharmacology 80
`
`Sioossoy 80
`
`Anlmol models 01 disease
`Clinical lriols
`86
`
`Baloncing benefjt and risk
`
`89
`
`
`8 4
`
`
`7. Absonption and distribution of drugs 91
`
`1ro nsfocol;on of drug molecules. Q 1
`
`Drug d ispa5llion 97
`
`Drug o bsorp lion 98
`
`Spe601 drug delivery 'y,'e m,
`
`10d
`
`
`8, Drug eliminott<m and pharmacokinetics
`D1ug me loboli ,rn
`106
`
`Renol ex.crelion of drug!. and drug metabolites
`Biliory excretion and enterohepo l;c circulation
`Phormocokinelics
`I 14
`
`
`106
`
`
`I 1 1
`
`1 I J
`
`
`vii
`
`Page 3 of 22
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`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`CONTENTS
`
`
`CHEMICAL MEDIATORS
`9. Chemicol mediators and the autonomic nervous
`
`'ystem 122
`
`122
`Historical o~pecr!l
`The peripheral nervous ~y~le m }'23
`Some general principle ~ of chemical
`126
`!fommi!l~ion
`Bo~ic ~Iep~ in neurochemicoilfonsmi'ssion ' siles of drug
`oelion
`I JJ
`
`136
`10. Cholinergic trammiHion
`M\Jscannic and nicolini, cclions 01
`ocetykholine
`136
`
`137
`
`Acetylcholine receplo"
`139
`Physiology of cholinergic tronsml sSl on
`Effecrs of drug s 011 cholinergIC transmission
`
`143
`
`161
`11. Narodrenergic transmission
`Clossiflcation of odrenocepro l s
`161
`Physiology of nOfodrenergic Irommission
`Drugs octrng .)0 odrenoceplOfs
`\ 68
`Drugs thor oHe·.::1 norodrenergic neurons
`
`164
`
`176
`
`12. Other peripheral mediatar" S-hydra.ytryptomine and
`purine,
`184
`5-hydmxy'ryp'omine
`Purines
`192
`
`184
`
`13. Peptide, and protein> a, mediators
`198
`
`Generol prine. pie, o! peplide phormocology
`B,osynlhesis and regu!olion of pep:ides
`202
`
`Peptide onlcg o nisls 20d
`
`P'o'e,n , ond peplide, 0' d,u9' 205
`
`Concluding rerno rb
`'206
`
`
`198
`
`
`14. Nit,;c o.ide 208
`S '05ynlheslS 0 OJ,ric oxide and ils control 209
`Degwdolion and cornoge o~ nitric oxide 210
`2 i 2
`Effects of nitric oxide
`Theropeullc opprooche, 213
`Clinicol conditions in which nilric oxide moy ploy 0
`'2 I .a
`port
`
`15. Locol hormones, inflammation and immune
`reachons
`'21 7
`The components of th e aCute Inflammatory
`reoCiion 2 17
`The Outcome of the inflommatory response
`Med lo lOt\ of inRommOlion and immune
`reocl lons 229
`CUrl enl I~-erapl es. bosed an manipulation 01 the
`immune response 24 1
`Polenliot new the rapies
`24 1
`
`228
`
`16. Antl -inAommototy and immunosuppressant
`drug' 244
`Non-s/eroidol anli -inflammatory drugs 244
`Anlogonisls of histam Ine 252
`Drugs used In gout 254
`Anlirheumofoid drugs 255
`Immuno5Uppresso ni drugs 257
`Po"ible fulure developmen"
`260
`
`Page 4 of 22
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`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`'" m
`Q o z
`
`DRUGS AFFECTING MAJOR ORGAN SYSTEMS
`
`
`CONTENTS
`
`
`25. The endoc;rine pancreas and lI>e control of blood
`
`glueo,. 380
`
`380
`
`Pancreatic Islet hormones
`Control of blood glucose 385
`
`Diabetes melli tus and the drugs used in
`
`treatment 385
`
`
`26. Obesity 394
`
`The homeosta ti c mechanisms con:ralling e ne rgy
`balance 39 4
`
`ObeSity Oi a heolrh proble m a nd pomb.•
`
`Ireolment \
`3 97
`
`
`27. The p,tuitary and adrenal cortex 404
`
`The pitUitary and d lugs used in th.,oPY
`d Od
`
`The ad renal corl e;:.: and d rugs used In therapy
`
`4 11
`
`
`28 . The thyroid 421
`
`Synthesis, storage and secre tion of th yroid
`
`hormones
`4 2 I
`
`Regulation 01 th yroid funclion
`Actions 01 the thy,oid hormone ,
`T(Om pod a nd metabolism
`42.d
`42.d
`Ab nor ma lities o! lhyroid function
`Drugs used in diseases or the Ihyroid
`
`422
`
`423
`
`
`d25
`
`29. The reproduct'" 'y,"'m 429
`
`Endocrine conlrol of reproduction and modulating
`dlug' 429
`
`Drugs used for contraception 439
`
`The uterus
`441
`
`Erectile dysiuncllan
`
`44 3
`
`
`30. Bane metabolism 446
`
`Bone slruc lufe and composi tion 44 6
`
`44 6
`
`Bo ne remodelling
`Disord ers o f bone a nd the drugs used in
`
`45 I
`
`Iroo tmenl
`
`17. The heart 264
`
`264
`
`Phys,ology of cOld iac function
`DfUgs that ollect co,d,oc funclion 272
`
`
`18. The .osculor system 285
`
`285
`
`Vasculor struc ture a nd function
`Conlrol of vosculor smooth muscle tone
`Vasoactive dlugs 292
`
`Clinical uses 01 "o~ooc l ive drugs 298
`
`
`286
`
`
`19. AII>e rosc:ieros,s and lipoprotein metabolism 306
`
`Athelogenesis 306
`
`in the blood 307
`
`lipopro:ein tronspo"
`l,pid·lowe,ing d' ug' 309
`
`
`20. Haemostasis and II>rombosis 314
`
`Blood coogulollon
`3 I 5
`
`Drugs Ihol ocl on the coogulotion cascade 317
`
`Plalelet adheSion an d ac tivation
`323
`
`327
`
`Fibrinoly,'s ithromboly'i')
`21. The hoemapoietie 'y,tem 330
`
`The hoemopoielic sys tem 330
`
`331
`
`Hoemolinic ogents
`Hoemopo,elic g rowth factors
`
`336
`
`
`22. The respiratory system 340
`
`3 .4 0
`
`The regu lolion of re spira tion
`Disorders o f resp lrO lion a nd th e drugs used in
`
`3 4 I
`
`Ileal menI
`
`23. The kidney 352
`
`352
`
`Outline of renol function
`The struc ture and func tion of 'he nephron
`Dlug' aering on the ki d ney 362
`
`365
`
`Dlug' wh,ch a lter the pH of the Uflne
`Drugs which o ller th e e;.:crelion of organic
`molecu le, 365
`
`
`352
`
`
`24. The gastroinleslinailract 367
`
`The innervation and the hormones o f the
`gOSlroinleslinol IrOCI
`367
`
`Gastric secretion
`368
`
`Vomi ting
`372
`
`375
`
`The mOliliry of Ihe goslro,nleslinol Irocl
`Drugs for chronic mnommOIOry bowel dIsease 377
`
`D, ug' aHecling the b iliary sysrem
`378
`
`
`Page 5 of 22
`
`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`CONJENTS
`
`
`THE NERVOUS SYSTEM
`31 . Chemi(al transmission and drug aChon in the central
`
`neNOu' 'y,tem 456
`
`Chemical !.ignolling in the ner-iOUS system
`458
`
`Torgel ~ for d~u9 oelion
`459
`
`Drug action in rhe central nervous !.yslem
`The clo~sificotion of psychotropic drugs 460
`
`
`457
`
`
`32 . Amino acid transmitters 462
`
`Excitotory amino acids 462
`
`Glutamate
`463
`
`Gornmo-ominobutyric acid
`Glycine
`473
`
`470
`
`
`33. Other transmitters and modulators 474
`
`475
`
`Noradrenaline
`476
`
`Dopomine
`5·Hydraxyrryptam ine 480
`
`Acetylcholine
`483
`
`485
`
`Purines
`485
`
`Histamine
`Olher CNS mediolo" 485
`
`A finol message 488
`
`
`34. Neurodegenerafive diso<ders 490
`
`M echanisms of neuronol death
`490
`
`!;ehaemlC broin domoge 493
`
`AlzheImer 's disease
`49 4
`
`Parkinson's disease
`4 9 7
`
`Hun/rnglon ' s disea se 501
`
`Neurodegenerol jve prion diseases
`
`501
`
`
`35. General anae,lhelic ogenl, 503
`
`Mechanism of oelion of anaesthetic drugs 504
`
`505
`
`The eHeers of anaesrl,erio o n nervous system
`Effecls on the cardiovascular respiratory systems 506
`
`506
`
`Inl,olallon anaesthetiCS
`IndiVidual inhalaTion onaeslhetio 509
`
`51 r
`
`Inlravenou~ anae~rhellc agents
`
`515
`
`36. Anxialytic and hypnotic drug '
`The nohJre of anxiety and mea~u(emenr of anxiolylic
`activity 515
`Clos~itication of onxiolyllC and hypnOlic drugs 516
`
`Benzadiazepines 517
`
`Benzodiozepine anra90ni ~l ~ 523
`
`6o,pi.one 52 3
`
`Barbiturates 523
`
`Other po!enliai anxialytic dru9 ~ 524
`
`
`(
`
`37. Antip,ychotic drug, 525
`
`The nalure of scl,izophrenra
`Anlip,ychalic drug, 528
`
`
`525
`
`
`38. Dnug' u,ed in affeclive di,arders 535
`
`The no lure of depression 535
`
`Theories of depression 536
`
`Antidepte»anl drug' 538
`
`Eleclroconvul~ive therapy 547
`
`Clin icol eHecliveness of antidepressanl
`
`IreOlments 548
`
`Mood·'labili sing drugs 548
`
`
`39. Antiepileptic drug, 550
`
`The noture 01 epilep,y 550
`
`Mecl,onjsm of action of onliepileplic drugs 553
`
`Antiepileplie drugs 554
`
`Muscle ~pa~m and cenl ~oI ly acting muscle
`
`.eloxanls 559
`
`
`40. Analge'ic drug, 562
`
`Neural mechan 'l~ms of pain 562
`
`Analgesic drug '
`572
`
`Newappraache,
`583
`
`
`41. eNS ,timulants and p,ychatamimetic drugs 585
`
`Convulsanls and re spiratory stimulants 585
`
`P'ychamalar stimulant,
`587
`
`Psychotomimet ic drugs
`591
`
`
`42. Drug dependence and drug abu,e 594
`
`The nalure of drug dependen ce 595
`
`Nicoline and tobacco 598
`
`Erho no l 603
`
`C annobis 608
`
`
`43 . local anae,thetics 612
`
`l ocal onoe ~ lhelic s 612
`
`O lhe. d'ug' Ihal ol/eet sodium channel,
`
`6 16
`
`
`Page 6 of 22
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`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`Drug elimination and
`pharmacokine'tics
`
`Overview 106
`
`Introduction 106
`
`Drug _bolism 106
`- Phase I ,_,;.""
`107
`- pt."., II ,ead;"", 109
`-
`Induction 01 microsomel enzymes 109
`- F,n'-pan (pre'yslemic) meioboIi"" 110
`- P!..,. mocoIogicoily oc';"" d,ug me4oboIiles
`Renal exuetion of drug. and drvg
`III
`metabolite.
`- GIo.no."Ia,. hltrclion 111
`- TLobuIor I«no6on 111
`- Dilfu,;.., aero.. "'" renallubulo 112
`- Drve elom,""""" ~ 0' deooOia 113
`Ililiary excretion and enterohepatic
`circulation 113
`
`11 1
`
`Pharmacokinetics 114
`- Single-c-omporSmen' model 114
`- More complicohld kinelic modeb
`
`I 16
`
`OVERVIEW
`
`In 'he first pan of th is chap.er, w e d escribe .he
`main pa.hwoys of drug metabolism , facto" .hot
`mRuonee drug elimmotion by the kidne y, and bil­
`iary OJ((' l ion and entc,.-ohcpotic recirculation of
`drug'S . The s6< ond part presant§ a ~ impl pho,.­
`ma(okin tic model that de5<ribe. how.h <harac ­
`tel"i,tiu of abJo..p'ion ~ distribution, metabolism
`and excretion delermine the .ime (ourse of the
`drug (oncenlro .ion
`in Ihe blood wi.h d ifferent
`dosing mgimcnJ:.
`
`INTRODUCTION
`
`106
`
`r 'll." ~ linllnJl iOf\ i( lh~ irr~q.·r'lbJ~ \O§::I. 0 1 dwg from lhl! bl1dy: il
`.~... roo b} t .....
`,lf O("CS:.<"" . Inelanilll "m :,nl1 iI! .t.: crelion . Me t:lbol l!>.m
`
`invol ves t!n1.ym .c con .... a~i on or ont: chemical em il) to dll<;lther.
`when:ilS o('l\:lIon t.:onSiSLS or eliminaHon frum the bod) of
`chemically ullchangl!d drug or ils metaboll!o;!:>, TIlt: lllail1l'('ul ('~ by
`which druf.~ anrl their metabolites kave tho;! body ilre'
`
`•
`
`Ill!! k..irlncy s
`rh e hepalObi liary sys[em
`th e lung!' {irnporwnt ro r volatilelgascou:-. an'Il,:stheLIC5.}
`
`M o$.( dru ~!'o lea\'e the body in the: urine. u{h~r u nl'hangro or ~s
`polar memhnl lle:-, 5umot drug s art' s.ecrct( d InCo bde \'i ;) I~ I m~ r.
`but 111 0" 01 Ihl!sC are Ihen reahsorbed fro m Ih.:: illlcsri nc. T'here
`l e.g. rifampicin } where racca l k>~(
`<}r(", however. ill ~aCl nce::.
`a,cnunb lor the 1.~ limin atj on o f a !:Iubslamj al fr,(I:li on o r unChanged
`dmg in hea hh} IOdi\'ldllal ~. and faecal elimination or drug..;; such
`;)0. di!!l..l1;in
`thai
`'1rl.' norm all y
`t:<creled
`in urin e become:)
`pfogr~c, i\'e l y more imponam in patients wi th advancing renal
`raih.Ift:. E\c rclio l1 \'i a th e lungs occ urs on ly with highly volalilc or
`g;l'\oCOlI::. ;,tgl:.'nh (l!.~ , g.eneral anaeslhetico;;j. Small anlllUniS of ::.01111.:
`dmg.'\o arc J b.o e xcreted til SccrelJ OliS such as milk or sweat
`Ehmlnalion b) thc.e routc!! is qu anliw,livel) ntghJl ihl1! cornp:ui..~
`with r(.! nal t!'.\l..rc l,on, ~llhoLlgh excretion into mil k can ~1IC' I IiTIt'~
`be illlporw.llI t'C('au~ o f I!ft"tc ts on lhe bab y.
`Lipophilic )tunS!;}nC';:$ are nOI ClilllinJ.tcd clTi~lc l1\l ) h'. lhe
`J..Jdney. ('o n)l.'quc:nli). most lipophilic d rug:. .lIe mCl3hoh::.ed tv
`mon: polar prOOUt.:1 5, whic h are Ihen excrc.to!d to unnc . Dru~
`melaboli:am ()(..cu" predontinanll) in the 11\':(, «.",......""311)' b} I~
`~y::.[em Som(: P~ 50 enz Inc~ i.lR:
`nftld,rl)lII f' P.J5() (e}'p)
`impon aot p3t'1 in ~.. ('ral :"ynlhc.ilc
`e.\lrJhl!patl~ and play an
`PillhwHYS including :ilea-o id bios yntheSIS in 'he oore n31 gland,
`the bi,,'ynlhl.':-.i.. of prosla~ landin ': (P(j l ~, pr~r~.")'d j.,, and
`Ihromno'\i1nes (Ch. 15), and posslhl )' o f cnd{)lheliulH ·deri\"('d
`hyperpolaris lng factor ('EDHF : Ch 18), bUI her\! \\,.(" sh;:lil be
`concem!O:"d with ea(aboli ~m of drugs: by
`the h~p:.ltjl.' P..t.50
`
`!> )'St~IlL
`
`DRUG METABOLISM
`
`Anim;d" ha\o;! e\'oh:e:d complex ~)!>IC Ill!lo
`lhjl\ d l!w xl fy rort' lgn
`chl.'lntCals. Inc luding (arcin oS! en ~ anJ 10>'l n ~ prc~ 1I1 in PObOnoW.
`plants. Dru p art a sp-ccia.l case of such h.)r':lgn d1eml ... ili lind.
`Ii!.:..:: plant ~I killo id:a . they often exhibi t dl Sll l'h.'1 r hir;tlit ) (I c . th('~
`IS more
`th an one siereoisomen, ...... hicll al fccb
`thell' o\'('"(all
`
`Page 7 of 22
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`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`I.:du~' lI on (lr
`lIJdroIy!iI~ ). Jnd !h(" prf'ld U"~{.' Jrt: o f1en HhJrt' ("heru i\. itlh !'."i:h "jj\ t.
`. . ~ ... , p<lraJ ~):"(i,,' ;dly, ~ l) 1l) t;' lim(' ~ )n Ie' 10"i..· o r ("Jr... in,.~(. n il
`", m.: parent dJu~ I)h:l'>t,' II redCli()I1~ :"'fc ~~'nlhc'tlc t:tn,Jh nlh.: ,
`In\·"I\·1.: ...:onJu~,;'III ('I n. ""hl(h usua{l~, re-:-ull:-
`In
`imh'ti v t;:'
`(dLhl) II~.h the- I'(: <ll'e C'xceplion:::. fOf e"nnpk \he xti\c
`tnelilbnlilc ui' mino"\idil, :... P01:J::;-.;ium channel iKli ... at.lr
`to Ire-at St:\-C(e hypene-n<,inn: Ch. 18). Ph:..."e I re ""c l in 'l~ 0(1('11
`im •• lIlt"
`Ihi ..
`'(un';lii)nJ.li:-i1Ii ol;·1.
`group the-n
`... ~ the pc'In( of ,m:... k
`Iht'
`f~"'r
`' •• ,,,,'i,,'g :;'),sll'm 10 ~llJLh :... substiluent .. u\:h ;.,s i:l tK" lIfnniclc
`'lJ.gn. lIsUJlly decrcJsc lipio ~(l!ubtl i l). (llu:­
`
`!'erve.:;
`
`BlJ(h
`
`_
`
`1:1).., <: pl:l.:t lll()inl~ in (he li\.i.'f,
`
`SUtTk' J nJgs ~I"c' nJ..:I<1boI J"4.:J jli pl a~ n1J :c.g. h~JrllJ~ .. i".-, t
`
`'.......!h'.niiuITI h~ Pi;):-In fl ;::ho llll~q("L) -< : sec Ch.
`I V,. h'l1 .t;.
`
`various pr,.I;l;.,no.J): .~••:l' eh. I ) 'J or gUI Il'.£. t~raJllin(',
`
`'>. 221. \\an~ hepalic drug'llIcIJbl) h ,in~
`
`Chs
`1II(luJing ("~ Il........ hrvm(! p..):')O,
`ill Jh...
`
`,)f.... 10IIllvJded
`re-li.:ululll. They
`Jfc' ofl~n .:;tlko
`
`e-lldoplll~mi(
`mal'
`h':C8.U"t:". on honwgeni.; ..lIi.lll
`\'nZyntt::-
`ilnJ
`
`.... tnlli. , ("enlilrug"H;,'l n. (he cnJophbtnic rtllclI!UHl i~ br("'k~n
`
`\cry sm<lll i"ragnle-nlS rhJ\ sedlmenl only aller prO [~ln t'1.'J
`
`"'~!jI<",d ce-nlrifugJr't,n in rhe 'rnicro;'(lnl:JI' rr~('(i\lll T o rc~dl
`
`J1lt.'t..hfllislngo.:'nlyllle ~ ill life, J drug Inll~r Cfll.... Ihe- p Ja'tll;)
`
`
`• .,t..,,,, Pol<1S rn o kculc... Jl1 (hi" Ie..... rt' :ldil~ Ih;.w nOIl -po LII
`_,""ok. ~x.(:l'f'( wh\'I(' (hdC ,HI' "p('( i fil' (ran" pOII lll('.:h.lfl i .. m )
`7). ~ illlruC"('IIt,I ~lr i1ll'l;) b (l li"-m i... in gt'lll'fJI !r..... <, illl pon.1I11
`polIr drugs Ihan fo r lipid· ...o luble drug". ~l n\1 Ih e l...'fllICf Il' 110
`be e,cr~ltJ urt~-h j ngl' J in ,h(' urine C nn\ C"r:'-e !:, nl,n·j1t"l l.lr
`
`DRUG ELIMINATION AND PHARMACOKINETICS
`
`8
`
`J ill": ' \.,In rC';IJt!~ ~I(\·e .... 1111 r ..h':cI Il,l.,r l'II L.\lllC-' but Jrt Cllllllll Jll.:ti
`Ihc ).,.,IJne~':- b ";'<L ,lU'A' pI r.1 .... .. l\t·
`\·t::rv illC'lllu~nll.\ b \
`tu nu)ar
`1 ~ ,lh..nrr(i\..I1l ('"... C p . 11.2 tU:!!.l'V).
`
`Stereoselectivity
`"\I~'h iI" sOla\ol (eh, P i
`j\l"'H~' clllli ..".1 n~· ; tnW>rlJlIl Jfl tg'"
`warfarin i ell. ~ O l ,mel cyclophosphiilUidl' (Ch 501. ~I rc nll X(lI rn
`or .... IdC'l)i ..lll llor'r... Ih<;c .-nmpPlk>Ill j or Whl<::h Jll f e-I 1l()1 ')l1ly III lhelr
`ph;)rlll.J.("pJyn;unlt.' ;IC(I\ll> bUI ']1 ,0 ill (heir IllCl ah~'1 1';ln. whic h
`)"oillm' 1..'<Jll1I.lkl~ly di.)(itlo.'( p::lIh\..... :...y,. S ~· \('r,t1 .'Iiniol! y
`111;1:
`l :- ~)(,"C ll"l<: inhihltion or
`IInpnrl;l!l! drug intcr<lUlon.. Involvt:" "le n"
`)} )...' l ;lhnli .. tn " t" t'l ne drll:; by :lnother (Ch. '\(1', In \.()I Tl~' I..J. ..~~ dfU~
`Il)\i...:i[y .lr'I~'·I"," I,' bC. Ill"inl~' linled 1(1 \)tle nl l he ,lert",'m Olllt'r :oo.
`lIOI nf,:t.· .. .:.\r ily lh(" jlh_lnn .l t"ol(i ~ it.'jJI~ J(li \{"
`l, nt.'.
`re~ul.l ! \)r~ ;:Wlh<}rilie.) 1\1" \\ Uf)!C
`th.11 flt.. '"­
`rt'Jc Il l ' .Jhk,
`pure­
`.. hl 'uld
`ro n q !<o l
`"It'reoi"(lllk' r..
`10
`.J l ... ~d
`\:(')1 n p il l .111 (' 11';,
`
`\ Vhcre
`
`drug~
`l h~,l'
`
`(11"
`
`PHASE I REACTIONS
`
`THE P450 MONOOXYGENASE SYSTEM
`
`Noture, classifi<otion ond me<honism of P450
`enzymes
`( v I0••:hr0m.:- P45(1 cnzytn\:".. ar~ ilat'l]) 1'1" ·'It'ill". COll ll'n" ll g J br ge­
`lamily (' .. upcrfJ-mily·) ui" reli.Jlt'd bUI d;:<i flil I n''~ lI k ..
`I(';l. ll
`rei"c'lTcd It} a.. C\'P lollowe-J b\ it de-rinin~ .... cl ('1' IlUmber.; ~Ild
`kllC! I. Thl:>\:" enzyme.) dil t"t:r IrOll1 01'1(. ;lllol l1t'r in " mUl l) <J ..·id
`:-eqllfllto;' . In r(' gliLt li~.n t>y Il;hibil~ll ' ,lI\j 1IIdUI.-In),' d W:('I'l [ " :m ..J in
`111.:- =,p('(" i(lcil ~ ,II tilt..:
`'I"(.".K I ;\\II') lh .• l lhn' ""',Ilill >..c: \\.{"(' ~t" I~O:l tl
`;11. 1()1..}(1 r~"\r ,1 rC\ll- \~ I . l) l fll? ....C'nl m~· lll bcr~ of In.: rJI UlI ~ hJ\C'
`Ji " llIlll. h UI \.1([("1) oYcrl ,'pf.'ill g . .. uh ' tr:lle .. p c ..'Jr.CIlIC-S ",' u h ,,(lOll'
`t l{her nut ;1,(
`..ub:' lr~t(;:: ;\.. e:--....... h
`C'I1L~ nl C' ,ll~l i l1~ (l1l
`l ~ "" " ;:('
`
`Drug
`
`Phase 1
`
`OXldallOil
`Hydroxylation
`OealkyJalion
`Oearninalion
`HydrolyS!S
`
`Example
`
`Derivative
`
`Phase 2
`
`---,:----+ Conjugate
`
`COlllugatlon
`
`OH
`.I HO'·)H
`
`GOOH
`
`0 - -(
`CDOH
`
`o
`
`COOH
`•
`.~ OH
`I
`I
`'~
`
`-
`
`SalICylic acid
`
`Glucuronide
`
`Fig, 8,1 The two phases 01 drug
`metabolism.
`
`107
`
`Page 8 of 22
`
`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`SECTION 1: GENERAL PRINCIPLES
`
`
`different (3h::S . Purifi calton ~ f P4 50 e Ol'y me ~ and eDNA
`(complementary DN :\) cloning Corm the ba 51~ of (he (,lIITeR!
`cla~siflc alion system , Ik hi c h is based o n amtn o aC Id :,eque-ncc
`simila,rTue$, So far. 74 CYP gene famIlies ha .... e been described. ('If
`w hich (hr~e !'nain o ne 'S (CYPI, C Y ?::: and CYP3, <lfe In vol "t:d \11
`drug meca ooli sm in human li\·er. CYP\A~ IS o ne of th e main
`c:: nzyme"), Examples of Ihuapeulic dru g:: lhfll af~ 5.ub.~ lral e ~ for
`CYPI A2. and other imp:manl 1>-.150 ~!l zyrll{,5 ."ttHJ Ihelr subSLrates.
`are shov.n in Table 8. 1 Orug o;o:'ldalion by !he Jn O'lU{)xyg.~·nas.~
`P450 syslt':m requlres drug (& ul' S lr~le, "DH ' j. P450 e nzyme and ,
`in addllion. molecul ar ox yge n, NADPH and a n 3"'0prOleln
`(N AD?H·P4 sn redu':IJSe). The me.:hamsm jn\ol \'(~s a complex
`cy cle (Fig. 8.2). l'u( L11f ov~r~H ncol e (f~c l o f Ihe rea(;lion I!I quile
`simple , namely Ih~ addilion of one ':Il om Q; o.\y gen (fro m
`molecul ar o x ygen 1 LO (h e d rug lO form a hYl1ro.x y l group (pr oduct.
`·DOH ·). lhe other al o m of oxy gen being con \ e ne d \ (1 w ;ILer.
`
`..,. Th ~ p .: ~r! ~ n Z ~ l n t' '' have '''hq tJ~ loec1l.J1 OlO r 6 ' . r!' \ and [he ~"'IJ, ed
`forms C"OfnDme "'dlh citJbon nl4V1olO, idr It t rmm ..: r id. ~ ,.m,rx,o...l1d (ht:-I ~
`.p' J WHh .:.h~orP ll on r eab
`r"I~ ar ..I SO nm ilJl1 jil' .1<17-..152 ' ·f.I Tilt 111)1
`t: '.'\dence Ula1Ihe. ( IS nh'll ~' Ih::':1 o n!!' k'rm .J t "U'It.. hrome PJ j O': l rru: ~f, · m
`
`Product (DOH)
`
`Drug (DH)
`
`Fe
`
`
`P450
`
`Fe>­
`DOH
`
`F ....
`
`DH
`
`e
`
`0 ,
`
`F "0.
`DH
`
`NADPH·P450 redv clase
`
`Cylochrome b"j
`
`Fig. B,2 The monooxygenase P450 c yCle, P,V,Q cunlC! noltlg
`fernc 'ron (FeJ.' ) combInes w ith a " lQlecu;r: ot drug tI>H).
`recclves M electron /rom NAOI-'H-P4,)O rrxk.cta50 wh rch
`leducl!S Ihe 'ron 10 F-O"'· . comolncs w ttl
`eCl;tar oxyge n. a
`prOlan i:lrId a sp.cood e-oeClron (ClttJer 'rom NAOPH .P.\ SO
`reduclase or frnrn cyloch r~n e b. J (0 Ion" an Fe~· OOH OH
`complex TIllS con bfne ~ ...... '11', d '10 1her p rolo" :Q YIE!'IO \'Iawr an d
`a femc oxene (FeO) J' OH COmplp. x (F eD.. . ex lracl.s a
`hyarogen alom h om DH W !1 • ~ t1e forrn<l hon 01 a parr of short·
`hved tree ra· ca ts ~ see lex' \ bPra t, f I iI()m :he 00:
`I .... I'
`1, .]11 o f P4SQ en! ,.
`l ( • .J( '
`ox ..urs ~d
`_ , _ 11 ,
`
`108
`
`Table 8.1 Examples 01 common drU9s that are substrates
`for P450 Isoenzymes
`
`Isoenzyme P450
`
`Drug
`
`CVP1Al
`
`CVPIA2
`
`CYP2A6
`
`C YP2CB
`
`CYP2C9
`
`TheophyllIne
`
`Caltelne, paracelamot. [acline,
`theophylline
`
`Methoxyflui ane
`
`Taxol
`
`Ibuprolen , phenytOIn. lotbulamlde, warfarin
`
`CYP2CI9
`
`Omeprazote
`
`CYP2D6
`
`CY P2El
`
`CYP3.A.4 /S
`
`Clozapme. cod eine. debllSOQUlne,
`metoprolol
`
`Alcohol, enlturane. halotha n e
`
`Clctosponn . 10Saf1an. nlfedTplne.
`lerfenad~ne
`
`From: PIChard el al (1995) Prediclabrlicy ot drug melabolism
`from In vl110 studies. In: Alv an G at al (edS) CO ST S'
`conference on vanablhly and speclilClty 10 df\lg melabollsm.
`European Commission, LuxemooIJrg. pp. 45- 56
`
`v., . lh 3 lI~ hykh",· I. I .lth rf"l'II' . ll.
`. , b~~I ~_ · It)n I.,,J\ I I\'Jl!hC III 01 r .11'1
`lhr:
`tn ~ :lJ? l! nI I::ot'e belu \A. 1. \.·... l,jwS fI IIhdl In lhe " b~; lpuo l) In :J ... tmURl
`Ir lJ
`IrQ I!I ...''' I" lol l'. 1111: .
`
`Cy p (. ! ly rt'"~... fl tl.\'l! ll"KlUt" n ao\ pf nr<" rl1~ ~ Ih;il ~ < fund.llllefl t,lI.otht:J
`d l' ('r So! II. n':I II)ll~ Tb<\c '\i'l .• 1t' I,', Ihe ' <.!f .lh!e ,["I n ~1;JtLI:' ,b'l,J.nl1{'. , of l!!r
`h.le r , H,'IH . •,IowJoCh Il e~ 111 III' u..: I.Jhr-Jr"j .:-ornp l("" l'; ""lit! ~ '\: "~ ,I nd s l Dd
`\/" '1 .•• 11 "'" h,cn II c.,.~ .Idnl)l retli'ler II {)('nlQ C1 l'tC' x... ·~-Wrd.n.'tt" ~' liQlJ r<lII '.
`'AD?H P~.fjt, . tdU( I... ,c s\,t~" e!t .Int': 0 1 buill C" t'('I '
`li S "c«I~d r(or ,...
`Ind
`(he P45 0 l ~<hr
`rc<.ll·x
`r c~i or( , Ih l!
`~, ..
`('\ X IJ il l,(l
`, I.'d e-
`"'))" I ~I: I ' I.tl"'tc4r.1\ i l')F\ .!: h.lt-Ift If' )11 ,"\('. 11" , ,, _ ~ «nJ u l lol. l l , n \~l lh .;u!;Nntr
`,u ll\. ~ l h·n The: k IT l": 1m .] tft: lo
`, In rrtt PlSO i"
`,J 'J ), !' (:/! II
`1111,..1111\=
`.1
`lTi.)ml: . •tI
`~i k·1I ' pm (,lrl"l
`", fit:. \;l~nJ\n£, OH. a C" rlIUrti h 'IiQr\.11 c;
`::"
`C'-·i · \ l; rl~ 'I' ,: k IP,' Fe"
`Ir..n rft tht ' h lfl':. ~pi n ~ Ll t' , 1Il", 1;: 1I1~ I I r:
`, I." ~ ,
`rtrJu,, _ Rl: d ll" I ~,"j " ,1n l Ft!" '- I,' FI:-' I ~ .ld lti'Ie:J t~ a "' .rile t>1«u_
`\, III.:h I' Te1.J.) uJ 11,,,11 N )'OPH l e k ~ !t {"lll Jo,lurl 10 P-l50 " !II llir
`" ,"'.)]'ru're l'l l\; VPH · Pol $U icduCI ,' '-C M nlt,,- u l:ll
`'l ,y~("n b lfl m. rllr
`h',I ... <J Fc- - I)H _. " n ~"(' \ h) 1: . til .) F~· · O _ OH r.:{"If1'I jliex
`rhl ~ u'
`..~·,·c rl4~ ,I "l'C'I..,"fl;. -=I~I I..II (. " II N A DPH-\' l 5t. I CJUU oDt" (i'l aht m .l.h~
`lr' llfI \ y •• ..; I II ~' " ': ;,.1 .'.'J l
`j"'I.,[O tl . 10 y lcltJ .1 per. I\ ldf' .. (ifl1 ~'\.
`!'Ire.l"~' ''' Ihe Fr" UUH Uti
`F~· -OOH D H
`,IIy-lll:. ·:· 01 J ~l·~ \" I.\ 1'1" \' ''-
`l r~ I' · Jnll' ,·L"t1Ifb,.
`\· ,!li,l,.,
`I,' \h,lJ .... .Url .,nl' .1 .': I I~,
`' (Ar ne:
`d (' 0 1' · II H th'O r ' i'JroIfAh h ~ dh'~ l:::' I , lllllJ Irunl [l H II> form:1 ~':1:r '"
`11":111 _1, '111 " lor h~tl .... lh D' .LlllI h_'~'O H o· .'~ 41 111", l he h" P,I" O H' I. ~ JI
`I,' 1<,. it hy J~,,\ ;,," ("~[ ,I'tJc I OO H ) •... h ,~ h \' 1.; lt J\ c, 1 ''' ' m W~ COlltp
`\
`'.\ 11lle't:.:t>troill ILltI hi P "~. ,I, Ih I," .II .!l _•. lI ot'
`
`P450 and biological variation
`The re ~m~ IInpL\I"I:lnl Va{l , rI10n~ lrI the e\prc:" , roll anJ f egu l.lf[ on cI
`P4:'0 ~nLyrne" ~t \l..:!c: n 'pec) \'"" For Ilh [J n(e
`lhe <lcll vauoo
`p:llh w<.Li " (" lal.11I 1 dlel:lry h.denl...·~..: ll c dllllnc,- \ lornlCd \\ ht.."
`
`Page 9 of 22
`
`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`- - - - - - -
`
`DRUG ELIMINATION AND PHARMACOKINETICS
`
`8
`
`meal is cookC'd) tl> gcnoroxic prodllctS. Involve" Olh: m~mn<:' r (11
`me P4S0 su,xrfamily (CYPL;l,,:~, that is .:on.Qi'Uli\el.\ pr(.' 5t'11l In
`human.~ and r::l\S (V.hl..:h d~\'dop .:olon lu;nO~ir s afler \rt::Jllnenl
`with su( h ~ mi n''' 1 but Ilf'! in ,:)nOmolgll::- mOll k..:: y-; , wlli.:h do
`0(1). Such 'i''IIe'cW;: s d l l(en:,n..::~:. hJ\'C' crtl c iJi illlpl i<:".ll ion' lor lhe
`choke or s['t'cie ..
`til he" n,("d I(lr [oXlci!: ;Illd c;lr,:inogtn icII Y
`teilillg during [h ~' dt wl(!p;J'clll of neW lio,p fo r L:<:C in htJman~
`Wilhin human population" [here are major s.o urces of
`ioacrindividual vanatil1n
`in P450 enzyme, (hal arl' 0 [ ~t1!':;11
`lmponjnce
`In
`The-s.e
`include
`Iherap~lHics
`~C'nl' !ic
`poIrmorphi"tlls: ror ~xompk. one \"ariom of the gene Cl.,.,2D6
`~ to poor or e'len.<;'IVC hydrox.Ylalion ot' debrisoquine
`En"ironlTIC'nlal (a..'(or" (eh . .; I) Me
`;)\sn
`impllrlJnl Enzyme
`ailibitors ;..nd illduc,-'r' :'1 ": pre::'-(" l11 in thl:.' diel Jnd {'nvironnK'!l{
`for e,J;iJmpk, g.r<Jpefrui! JUI,-' t' anti 5t John's won ! u_,>ed 10 Ire.11
`'=Pre~,ion in 'all<:'rn;Jti\'t::' n"](.'dKinc ) innibll drug n1c-ta1:"loil::m
`.eaiing 10 pOlentiall) JI ~ <:I~lrOu, C-Oll ~tlCnc-e ' . ,nclud lnf , .Jrdl......:
`dy:ilb~1hmi,l~ Ch. 51! \\-her'-'Js B ru~":'el:: ~P{OJh dnd Cl g.~ rC II ";
`5{00ke in~111...·t· P..j:"O cnL\-rnC'
`
`Inhibition of P450
`InIubilQ~ elf P..j50 J IIT(' r 111
`loward dill( rent
`Ihell sckc-Li\H)
`isdonns of thc cm~m(' ~I)d :1It' ..:I ;.. -s.:-ili.o-d b., theif me~h,ln l <;, !n of
`a:ulJn. Some dru~" L'nmpec?
`for [hi J.L'li\ c "lIe' r.tll ,li t n("ll
`kmselvcs .~ub.~lra{cS {e.g quinidine IS J p'
`'\:till\'c
`is not a '-.ub"lrale: 101
`ilmihhor elf CYP~D(l 1:"lut
`il}.
`!~ on
`competilive inhibitor, 1Il.2'lude drtl~ ) :,u.: h as kptocon3~ole . wllil'h
`btM :J tight cornrk:\ With (he Ft."~ form ()[ the h:I<'lll iron of
`CYP3A4 caus-Hlg
`r,-'vCI"sible
`llon'(0mperi l lVf'
`inhlbllinn
`S ~\
`a Ute.! mecllani_Qll,biJ<;;cd
`Inhlb,lors rtqulre O\!dJllt111 by ,l
`N 50 en2.vme
`r \.1mple~ incilide geslodent
`, CYP,l ~\..jJ.
`6ihylcarbamnle (C,'P2EJ , :1Jld furaf~lJine , C,'PIA ~, An
`l!lGJ,lion product I t" g. d P0;'lul" l~d ~p0\ ld~ InI~IIT1 C' d I J II! o f
`podenrr) bmJ, LIH"Cl lt' nll, It) Ihr: ~ n l~ lllt. l he r~'H :i ('I t" ~\'Ilidl
`1bCI1 dC"sUO\ <;
`ilo:.(' lf (·"Ui ...-li.k
`inhi billo n I
`,V!:ln~ clinlc:tlh
`lIIIp..1nant lJ1.tt'I.!.L'(i or)" h.?IWt·~·fl Jrugs Jre Ihe re~ull pf Iflhlbilion
`afN50 en/,) nle''' (<..a ell 51 J
`
`OTI-IER PHASE I REACTIONS
`
`Jriot all drug oxid~JIH)n leadlono:. exdu"lve-l} In\-,-'Iv(" Ihe P..j50
`tpttm. For ~' ;cJlnpk. ethanol I.' m~Llboli~t'd by :J "olllbk
`c,..pbslll i..: l· nz.VIIl('
`"kohol dchvdlo!:!en.J"c
`III <IdJitlon Hi
`CYP2EI. Othcr' L",epli\in~ i!lcludt' x;nthllll? ()xi(j:ht'. v. hivh
`6·IlI.:r...·:lpIOpllr!n...' I,Ch. ~9) ~ln.~1 nlf 'IJO.lIIlII,,-- ()'\IJ.I,e
`"lOln e: , 1(' '.!
`in;l..:-tl\'Jt (' ~ m(ln~ b)(J h)g.I(<tIl~
`.'IIIi,-"",I".,. " ·rO/JI lll r . .::: ./" r!rp \ I In"!lIl I/l,/IJe, ,L' I:' l !l\ II ~.nd
`
`"CI I\ ,'
`
`(h,ln ~1'\I J.U ; '1II ' ,
`
`1111 ("11 II 1;"l11l. F'll c\ :1 mp k ......arLlrin '(h ~ lt l
`j ,
`
`U {oo h, ("l,I)\-o;' 1~ Hl n 01 a )...,elone lu ;1 h~(llo\~1 ~rollp 0)
`
`
`tll'C f" " ill1.tI
`ill\ ; >l\-~ her,ill""
`III"
`11."lic r('(lCli(!lI~ do
`III o,-'cur in pl.'''Il) ~t Jod 111 m <.I(1)' (i""lIe... Bt)Ih (' ~h~r ,.md
`~ I ~ ) :l.tnidc' bond, Me ,u·,"' ?PlLbk It) h)Jnll)-q,
`
`PHASE II REACTIONS
`
`It' ~ Jrut /t10 1~("ule hJS J suil.":!.bk 'hJndk' I(: _ ~ _ J tn dro x\L Ihiol
`..!r .:I mlOO groop l, t'Hh~r in Hie parcfll ITL (}k ~lIk o r III a produ~t
`1?,ul!ln g
`trMIl ph;);, C'
`{
`'5u"'c prlbk 10
`;n':: I:lboll~;n, it 1"
`( onj u~;(l lim . I. e . o((J(' hrn t'nl oi J "- ubstlLLlClli t L\lUr - '{ hI" ~~nlh!!u ...
`) It'p is cal led a ph,lie
`II
`f\:.J..:II,)I1. 1 h..: rC ~ lI !ti "~ (,C:'nlu ~ .::tle b
`almost .11\~ 3JS phJftnaC log l(~I1\ In3Ct! \'e dl!tl le~ ~ l'fllJ ~()I u~k
`lhan it ... pl ...',,:ubor drlJ i!l ,-'xcret,:J in urine or bile.
`'file ~r(lup;) nlO~1 oflen in\olved in conjugale t'off nollo n aIe
`gilicliran}I ~Fig :3.3). --. utl2lt, nlt:lhyl. <.Kf'I \ 1 ~.I~ cyl .Jnd
`f.IUlal!1lon..:. Glucuronide h1rmali(1) Invnl \'c.~., ,tt l' 1\."rm:Hinn (,f a
`h,gh'encrg~ phosphate comr'.J und. uridlne lil pho.. pha,I( (UOP)
`I:
`~llIcur () lIic acid tL'DPG <\), Ir(im whi""l g.l u(" ufi'ni..:
`,I..
`,
`lI"m'I,:l'red 10 In e1c":lI on , nch ,J\orn I ·, 0 or
`\ un Ihl!" ~1I1
`
`~ir -o ;1 L
`
`\..:'"
`(
`_~ f , t~ =fi
`(~
`,or ". ~ut.·h oJ '
`
`re ;}ct )(If\ '"
`I rtu1;)1l· r,I:o.l', v.hi.:h C3IJ!~ ';'; ~ th\: ~ t'
`, Ub, Ir:U': ~pe.: i t-' ':'' l!Y c'lnhla..: im: m,ln~ drl l~ ' :
`IHOit-•. 1' _. S \'\~r,,1 In11"-\r; .w1 Cl!dOgL IJlI U'" ' t..!
`1'_,lrubtn ... nd JdrenJI L"0111.."'O '- Ja o ,.-h J.r L JI ~f' r
`'JOlt.' , :/'I cm.
`,.),,": L'"t ~lJr,pn .H1J merhylalH'ut 1~.J\IL ()n' " I.. ur w Hh ac.tl\\ '
`~' A
`.I1.J 5 , ;:ld""I1G ") methlOllin,,'
`fe c pe':II \'I. !). ,,,,1 1;'
`; dOi',lr
`cl1mpI'lJnd,,_ i\r1Jn) \.11 lh c: "e ( !) nJ U~,~II ') n re,-Kllon ~ j~ l llf ill 1~C"
`II\-cr. but oLher 1I:O;'iues, ",uch
`;,.;
`lunf :.tnd kl Jn(' v , ~n: ,_IN)
`
`INDUCTION OF MICROSOMAL ENZYMES
`
`..j:- l ethanol .CII.
`A num1:"la of dru.£5- _~U..:~ :," rifarnpi('io lCh
`:':', ('..lrhamazepine IC h 39111l('rcasc thl:' :} ~~li\'ll~ ot rlll C'f O')('IlI,1!
`O,'I,I.! ~ ~ ..Inti (('Il.lugall llg \) ~ tel1l-" \\hen ,IL!illilll_l.:.'r L'"d lC'peil! e~1':
`Ie.;. h('fll ''''l~ n "
`\l;!n;.-
`... ,If\l nt'\! Cn K
`('ht nll ,- al.,
`:t. ,rn elh\ !.
`"h\~folnJiIi t.' nt' I,Ll .;" h,,\c thi ' ~ lfl'CI. \\ hi.:h -': -t ll bt" w l\"'.l,u IJI
`Fl enrr :-:-
`..j
`J n C.lr l ~ 10 ft· ld HI(r~.he l it Ihe' rJI~ I.,r
`..;.h')\~:-
`b...·n7.PXh: ne Irh.:I;ll" ,!tqlL ~ d:l~s «!'ter.J - 1I 1\!1..;.' Jc'":'o!
`fh..- t'1Ied
`'"
`["..-Inl ",I II' :1' IflOLk U0r) ..lid i:i IL,.- Tt: <; u l! ,-,r if'r..:'It.' ..c:..J ,\I Hh(' <I'. ,'I
`[l)1 ...:r 'I~ ')lll al ':> n ~:I1~'; .
`
`;,~ J..:,r t", ' "< dru l:
`Ln l~'II\t lllduC11,>1l ":.;n
`<1.:-
`InCIC.!':-C'
`..",0;;'\1
`1()...... kH~ ThC"'re are drug-', 1m ~_x;)1Ilpk par3Ht3mol , t,.\;h("(( {11~
`
`UDP,u·glueuronide
`
`C ...'Curnfwl :-af"""t~r
`
`UDP-glucuronylt ra"-~I~. s
`
`Dr ug, (j,glucuronide COfljugale
`
`Fig,8.3 The glucuronide cOflJugatlon reaClion.
`
`109
`
`Page 10 of 22
`
`YEDA EXHIBIT NO. 2086
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`SEGJON 1 GENERAL PRINCIPlES
`
`10 ,---~---- ---r--------.-----,
`•
`
`Table 8<2 Ex.amples 01 drugs thai undergo substantial
`first-pass eliminalion
`
`8
`
`G
`
`4
`
`4 IJmol dose
`
`0.4 jJmol dose
`
`Isosorblde dU111raie
`
`Levodopa
`
`Lidocaine
`
`Meloprc!ol
`
`Morphine
`
`Propranolol
`
`Salbulamol
`
`F,rQ-r<1":-
`
`IIld'II"l\.,Ji..,1ll
`
`I"; generally a nUI"~Hlce in practice,
`
`ixC:1U'ot':
`
`;) lllllC.h 1:11~'~ r clll"e 1)( thc drug 1<; Iletded v.,hen il I" given
`Nally 111;111 w he!l il I" gl\ell hy olher roule"
`nnrl-.ed Indl\ IdU:11 \':1riaLion" OC('U\ tn the n
`lt)\1 or (Ir~t-pass
`Il1el:lb{lll"m ~ll ~I gl\en drug ("t?t' Ch,.5 r l. le"ulLing III
`ullpro:::di(l~hdll~ wh~n ..;u(h drug" are LjKen orally,
`
`Drug metabolism
`
`Phase I reactions involve oxidation, reduction
`
`and hydrolysIs:
`
`- usually Jorm more chemically reactive products,
`
`sometimes pr,armacologically active. lox.