The Pharmacokinetics and Pharmacogenetics of the Antiemetic Cyclizine in Palliative Care Patients
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1 4 Jul f P d Sp M Vl. 43 N. 3 Mh 212 Ol Al Th Phks d Phs f h A l Pllv Ps J W.A. Vll-B, BS, Ph, Ev J. B, MD, B P. Js, PhD, Pul K.L. h, MBhB, Rb L. Rbs, PhD, M Fhll, RN, MA, Sd A.D.) Mld, MBhB, d K Rd, RN, MA ll Phl J.W.A.V.-B., E.J.B., P.K.L..), hshuh Hspl, hshuh; Nus Mud Hsp J.W.A.V.-B., M.F., S.A.D.M.), hshuh; Dp f Md E.J.B., B.P.J., R.L.R.), Uvs f O, hshuh; Dp f Bhs R.L.R.), Uvs f O, Dud; Hlh S S.A.D.M., K.R.), Uvs f bu, hshuh; d Hsp Pllv Edu K.R.), hshuh, Nw Zld Abs x. l, hs, s l usd pllv. Is phks hv b pl sudd, d s bl phw s ukw bu vlv h ll lld h P4 2D6 YP2D6). If hs s h s, h bl f l l d ffdvs ffs v bw ps d h YP2D6 p. Objvs. T ddu h phks d sdv ffs f l d l hs d s bl h YP2D6 p pllv ps. Mhds. Pllv ps d uus l subuus S) fuss hd bld spls k d ffx ss sud du h pph sd s. Ah up f ps sd s v l l hd sl bld spl k. Spls w ld lud phk ps d YP2D6 s. Rsuls. S ds up: Th d qul ) l hlf-lf, vlu f dsbu, d l w ) hus, ) Lk, d 1126) Lk, spvl. Nus d sd ss w ) d ), spvl, vll d dd v wh p P ¼.76 d.11, spvl). Th d vll bl sd s ws ) d dd v wh YP2D6 p P ¼.2). Ol ds up: Th d bl ws ) d dd v wh YP2D6 p P ¼.37). lus. Pllv ps hv sl l phks hs pd h p ups. l bls l Addss spd : J W.A. Vll-B, BS, Ph, ll Phl, hshuh Hspl, Rlls Avu, hshuh, Nw Zld. E-l: jvb@dhb.v. Ó 212 U.S. P Rlf Publshd b Elsv I. All hs svd. Apd f publ: Apl 12, $ - s f d:1.116j.jps
2 Vl. 43 N. 3 Mh 212 l Phks Pllv 41 lud YP2D6 s h bl vd wh YP2D6 p h S up. J P Sp M 212;43:448. Ó 212 U.S. P Rlf. Publshd b Elsv I. All hs svd. K Wds A, du s, us, YP2D6 Idu Pllv ps f xp us d v. Svl dus usd b hs sps, lud l. If v psss, hs ds b ffv ll s v pvs bsp. M ds usd pllv ps, hf, v b uus subuus S) fus, d hs luds l. Th phks f l hv b wll sudd ppul. 1 Th l j sud hus ws sx hlh vlus. 1 l s pp fs- hs 1 p s, 1,4 whh ws dvlpd s dusdf hs pups b h Nl Aus d Sp Ads du h fs d sp flhs. 7 l hs hlf-lf 12 )f 13.2 hus 1,81 sd s hd h fv ds), vlu f dsbu Vd) f Lk, 1,8 d l L) f 14 Lk. 1,8 I hs l vlbl f % bus f hh fs-pss bls, d v ll pps h u uhd f xd uhd u <.1). 1,8,1 Af l ds, pk pls s hd w h hus. 1 Aldspdudpk f bu 7 L bu w hus. 1 A f 3 L s sd b lw, 3 L s hh, L s x, d, L s lhl. 11 Th phws f l bls hv b full ludd. I s huh b bld l h v bl l b N-dhl. 9 N-luud ls s huh b p, wh 12%17% f ds f l b xd s N-luud h u d 3%6% h fs, bu h ll sf f hs s ukw.,12 Fv h bls hv b fud huds. 13 I hs b susd bu fd h h h P4 2D6 YP2D6) hs l h bls f l. Th hs hdx, whh s h s lss f hs pp) s l, s bld b YP2D6, 14 d l s kw hb YP2D6. Abu 8% f us, % f M, d up 3% f h As d Pf Isld ppuls d pdu YP2D6. 16 Th kw s p bls PMs). N-PMs kw s xsv bls EMs). Suds shw h ls hlf f EMs hv lss YP2D6 v h h d f EMs. 17 Th hv b lld d bls IMs), d s pssbl h h hv s d ffs bw hs f PMs d u EMs d phps fl h wh llls f lw v. B vs h YP2D6, h dvdul s bl sus b fd. If l s bld b YP2D6, h bl f l h bl l wll b hh PMs, d phps IMs, h EMs. As Th p f hs sud ws sblsh h pls s f l d l pllv ps v h uus S fuss f l du h pph sd s, s fllw-up sud, l l f u f fv ds psud sd s) d s phk ps f l h p up. A sd ws d h YP2D6 p f h p d l hs wh l l s d ff d x. Hw fls k p suh sh s p f hs p ppul ws fuh, whh s pd lswh hs ssu.
3 42 Vll-B l. Vl. 43 N. 3 Mh 212 Mhds Ths sud ws pfd w ps. Ehs ppvl ws bd f h Upp Suh A Rl Ehs Nw Zld. S Ds Sud Th sud ws dsd sblsh h fsbl f phkphd sh wh pld ll s pllv ) d b usful suls, f pssbl. Th up psd 1 suv ps wh hd jus sd wh w bu s v uus S l fuss 1 24 hus) d w ud f ps dd Nus Mud Hsp, hshuh, Nw Zld. Rlv dph d ll d w lld f f bd s p f h dss h hsp, lud dphs, suh s h,, wh, hh, d bd ss dx; ll dus h p ws ul k hd k h pvus w wks, lud v-h-u d hbl ds; dl hs; d u spspbls. Sl pphl bld spls w k h d jus bf h f l s h) f D 1 D 4 f h fus. O D psud sd s), pphl bld spls w k, 1, 2, 3, 4, 6, 8, 12, d 24 hus. Bld spls L) w lld hld d EDTA) ubs d fud dl 4 p f 1 us. Th pls ws spd ff d sd 8 ul lss. All spls w ssd pl us lqud hph-d ss sp L-MSMS) hd spll dvlpd f h sud. Th d f h spl bld lls) ws usd f DNA x d s f h s YP2D6 llls. A fuh pphl bld spl ws k f lss f lv fu ss d D 1. A vlu f us d sd sus ws d h bld spl us vsul lu sl f 11, wh b l d 1 b ws bl usv dwsss. Ol Ds Sud Th sud vlvd ps l l sd s, h s, ls fv ds f l ds f h s d ll, wh w ud f h hsp, hspl, u. Ths up ws ud f h S ds sud. Rlv dph d ll d w lld s f h S ds sud. A sl pphl bld spl ws k f fv ds f l l psud sd s). Bld spls L) w lld EDTA ubs d fud 4 p f 1 us u h lb. Sl h fs p f h sud, h pls ws spd ff, sd 8 ul lss, d ssd pl us L-MSMS, d h d f h spl bld lls) ws usd f DNA x d s f h s YP2D6 llls. Nus d sd sls w usd h spl vlu x d ff. Asss A L-MSMS ss ws dvlpd d h l d l s pls. Th ll ss hs b dsbd dl lswh. 18 Bfl, spl pp ssd f -sp p pp b dd 1 L f d 1 L l sdd) l L pls spl fllwd b fu 16, f fv us >9% v). Sp ws hvd wh Lu 8 2. ll lu Lu 8, Phx, T, A) d l d f 3%9% hl.% f d v h us. Th ls w dd b ss sp us psv lsp d h s f l d f l. Sdd uvs v h f 24 L f l d 22 L f l w dd b l ss whd 1x. Spls wh s hh h h sdd uv w dlud wh blk pls d ld. Eh pls spl ws ld pl lv sdd dv [RSD] <14%). Rpbl RSD) d bs f qul l spls w wh 13%. G DNA ws lld f pphl bld us phl-hlf x. 19,2 Sud pps w sd f YP2D6 PM d IM llls us pvusl dsbd w-sp lll-spf pls
4 Vl. 43 N. 3 Mh 212 l Phks Pllv 43 h PR). 21 Bfl, l- PR ws pfd h fs sp f hs ss sulusl s f h YP2D6* dl) lll, d whl dupls, d sl YP2D6 f h YP2D lus vd subsqu sp s sul f plf f hhl hlus psud squs. I h sd sp, h 4.7 kb YP2D6-spf PR pdu ws dlud d usd s pl w-ub lllspf PR dsd d h PM llls YP2D6*3, *4, d *6; d h IM llls YP2D6*9, *1, d * Sud pps wh sd v f hs v llls w ssud b p EMs YP2D6*1*1). Th phk psdvd, L, d 12 dw ludd f l s us sdd qus, h s, Vd ¼ dsl s sds ), L ¼ dssd-s, d 12 ¼ l2)l s. Th l s k) d h sd-s ss ) w ludd f h du uv du h pph sd s us h qu Y ¼ ss 1 xp k x), wh Y ¼ d x ¼. All ssl lss w d u us GphPd PsÔ GphPd Ps, RAPHpAD Sfw, S D, A). Sud s -s ws usd f pss. Rsuls uus S Ifus Sud ¼ 1) Dphs d dss lsd Tbl 1. Th d qul [IQR]) l 12 f ll ps ws ) hus, Vd ws ) Lk, d L ws ) L k. Th l - uvs f h f h 1 ps shw F. 1 d hs f l shw F. 2. Th d IQR ul ) f l D 1 ws ) L, d h d f h s Ds 3 ws ) L. s f l, l, d h d s v ll fv ds d v Ds 3 shw Tbl 2, h wh YP2D6 p d usdwsss ss. F ll fv ds, h d IQR) f l d l ws ) d ) L, spvl, whs h f l l ws ). F Ds 3, h d l ws ) d l ws ) L, whs h ws ). YP2D6 ps w fu EMs, fv IMs, d PM. N ps ud h sud f hds.whhl l s v hs ls h ds w ld, h d IQR ) s EMs, IMs, d h PM w ), ), d 13., spvl. Th ws ssll sf dff h s bw h EM d IM ups P ¼.2). I shuld b d h, s s F. 2, h l s hd ll d sd s s ps. Ths wuld sus h h u sd-s s b lw h h vlus pd h. Th ws dff P Tbl 1 uus S Ifus f l: P Dphs d Dss A Ys) Gd Eh GFR L) LFTs Albu L) Wh k) Ds24 Hus ) Dsk ) 1 78 F Nw Zld Eup 83 N sd M Nw Zld Eup Rsd F Nw Zld Eup 89 N sd M Nw Zld Eup 9 Rsd F Nw Zld Eup 6 Rsd M Nw Zld Eup 7 N sd M Nw Zld Eup 142 Rsd F Nw Zld Eup 71 N sd M Nw Zld Eup 78 Rsd F Nw Zld Eup 7 Rsd GFR ¼ sd lul fl ; LFTs ¼ lv fu ss; F ¼ fl; M ¼ l.
5 l l l P P l l L) l l L) P R = l L) l L) P 4 R = l P l 44 Vll-B l. Vl. 43 N. 3 Mh P P L ) P P P F. 1. uus S fus f l: l - uvs ¼ 1).
6 Vl. 43 N. 3 Mh 212 l Phks Pllv 4 Nl L Nl L Nl L Nl L Nl L P 1 R 2 = P 3 R 2 = P R 2 = P P 9 R 2 =.2261 R 2 = Nl L Nl L Nl L Nl L Nl L 2 1 P 2 R 2 = P 4 R 2 = P 6 R 2 = P 8 R 2 = P 1 R 2 = F. 2. uus S fus f l: l - uvs ¼ 1).
7 46 Vll-B l. Vl. 43 N. 3 Mh 212 Tbl 2 uus S Ifus f l: l d Nl s, l Nl Rs Ov All Fv Ds d Ds 3 Assud Sd S), YP2D6 Gps, d Nus d Dwsss Ss ¼ 1) l L) Nl L) R f l Nl Dwsss S f 1), Md [IQR]) Nus S f 1), Md [IQR]) YP2D6 Gp Ds 3 M SD) All Ds Md IQR) Ds 3 M SD) All Ds Md IQR) Ds 3 M SD) All Ds Md IQR) P ) ) ) 13 *4*4 PM 6 8) 7..8.) ) ) ) ) ) ) *1*4 IM 2 1.3) 4 2.) ) ) ) ) ) ) *1*4 IM ) ) ) ) ) ) ) ) *1*41 IM ) ) ) ) ) ) ) 4.7.6) *1*41 IM..1.) ) ) ) ) ) ) 7..6) *1*4 IM ) ) ) ) ).7 1.) ) 4..2) *1*1 EM 3.3) ) ) ) ) ) ) 2.3.2) *1*1 EM 46).) ) ) ) ) ) ) *1*1 EM ) 4.36.) ) N spl ) N spl ) N spl *1*1 EM 1..2.) ) Gps ws df p ups. SD ¼ sdd dv. Aul. bw h ups f us P ¼.76) dwsss P ¼.11). Ol Ds Sud ¼ 12) Th d hs up ws 69 s. Fv pps w l; ll w Nw Zld Eup. Th d sd lul fl ws 77 L, lv s w sd h ps, d h d lbu ws 3 L; d ll bu w ps, h ds ws 24 hus hd ds f 7 d h 1 24 hus). Th d IQR) pp l L LF, wh F s l vlbl) f l hs up ws 33 Lk ssu wh f 7 k). Th d IQR) f h sl l p p h 12 ps ws ) L. Th d IQR) l l ws ). s f l, l, d h s shw Tbl 3, h wh YP2D6 p. Th w h EMs f YP2D6 subss d IMs. Th d l l s w ) h EMs d ) h IMs. Th ws ssll sf dff h s bw h EM d IM ups P ¼.37). Th d IQR) us s ws 2..2.) f h EMs hs up, whs h f h IMs ws..3.). Ths w sfl dff P ¼.78). Dwsss ss w ) h EMs d ) h IMs. Th ws sf dff P ¼.37). N f h 22 ps h S d l suds w l k d YP2D6 hb dus. Dsuss Th lu h phks d, pul, h bls f l s sps. W w bl fd l sbl phsv sud b Wlk d Kf 1 h vsd h phks f l sx hlh l vlus f sl vus ds f l l. Ou sud pps b h fs sud h phks f l wh v b uus S pllv ps. Th phks, h s,
8 Vl. 43 N. 3 Mh 212 l Phks Pllv 47 Tbl 3 Ol Ds: l d Nl s, l Nl Rs, YP2D6 Gp, d Nus d Sd Ss ¼ 12) P l L) Nl L) R f l Nl YP2D6 Gp Nus S f 1) Dwsss S f 1) *1*4 IM *1*41 IM *1*4 IM *1*9 IM *1*41 IM *9*41 IM *1*4 IM *1*4 IM *1*4 IM *1*1 EM *1*1 EM *1*1 EM 9 Gps ws df p ups. 12, L, d Vd, f l u s lud l s) ll sl hs pd h fd sud, h s, us vs. hs s fllws: vs. 13. hus, Vd 22.7 vs. 16. Lk, d L. vs. 14. Lk. Th ppl slhl l Vd u sud b xpd u ppul f fl ld ps wh lpphl du suh s l bus, h ldl, w dss d f ss sul sd Vd. As L d, hf, h ds usd ffd kdl dsp h pld dl su f u ps pd wh hlh u vlus, w b fd u ds pl. Th s f l l w sudd h hlh vlu sud. 1 Nl ws dd pls, pssbl bus f h lw sl vus ds. I h uus S fus p f u sud, h d l l ws lw EMs h IMs, sus s vlv f YP2D6 h vs f l l. Ths s fd b h f h sl PM p b hh sll. Hwv, f luss b dw s u ubs lw l PM), d h bl hd hd sd s. Th s dffs s w s h l p f u sud. Ths s sups bus L f hh L du s lkl fl lv bld flw f S fus d s L f l ds. Oh fs, suh s d f lv p, h b xpd ff L, bu w fud dffs u sus f hs bw h ups.., lbu s). Ths sus h sl f YP2D6 vlv wuld b lkl f l ds, bu hs ws vd. Th w svl ls hs sud. Fw f h uus S fus ps pld h fv ds f spl, k s f h suls dfful p. Ths ws uxpd hs pld p up. All ps w v svl h ds, whh hv hlpd h us d usd dwsss, k h us d dwsss vsul lu sl ss pu fl f l l. I dd, dwsss s fu f l dss. I su, hs sud s h fs x h phks d phs f l pllv ps wh v b uus S fus. Th phks f l hs up f ps sl hs f hlh vlus. Th suls f S ds sus h l b bld l b YP2D6. Hwv, h l l s ps l l w dff l h YP2D6 p. Bus u ubs w sll, h pssbl f lph fls psv) ss h s f h S sud d b fls v) h l sud.
9 48 Vll-B l. Vl. 43 N. 3 Mh 212 Dslsus d Akwlds Fud f hs sud ws full vd f h pbll Bll Awd, Nus Mud Hsp. Th fls f s dl, d h fud su hd d pu hs pj. Th uhs hk F Fdl d Jk Wlk f sss h ll f spls, h uss wk Nus Mud Hsp d h u pllv, d h ps. Rfs 1. Wlk RB, Kf I. Phks f l fllw vus ds hu vlus. Eu J Ph S 1996;4: Wlk R, Kf I. Hh-pf lqud hph lss f l d s bl, l bll fluds us sld phs x. hph 1987;24: Ku R, Kluh A, Ts I, Bus JJ. Phsll dsbu d bl v f hll d l. J Phl Exp Th 196;14: Wlk RB, Kf I. Ssv hh-pf lqud hph d f l d s dhld bl, l, bll fluds us ul d. J h B Bd Appl 199;672: Lu H, Hws EM, MK G, Khsk ED, Mdh KK. N þ -luud f lph s, l ph h bls f H1-hss hus. Xb 1991;21: M LM, Gs, Bbh J, Hdf J, du Plsss J. Puus bsp f l d s lkl lus. Eu J Ph S ;24: NASA Hu Rsh P. Hlh Hu usus P. Evd bk: Rsk f hpu flu du ffvss f d. Hus, TX: Ld B. Jhs Sp, Kf I, Wlk RB. Phks f l f sl ds l ds hu vlus. [bs]. Ph S 1998;Suppl 1): S146. [Abs. 229]. 9. P DM, Wbs DR. ll phks f H1-p ss h hss). l Phk 198;1: Mdsf Vld TM dsh 211. AFT Phuls, Aukld, Nw Zld. Avlbl f hp: Assd Db, U.S. Fdl Av Ads. AMI xl du f f: l. Avlbl f hp:j..jb.vxldu Dl.sp?dd¼38. Assd Spb 21, Hws EM. N þ -luud, phw hu bls f dus wh up. Du Mb Dsps 1998;26: Dus M, G I, Huh E. Bsf f l huds. 1: Idf d lss f l d s bs bls u b s hph-ss sp. Xb 22;32: Hj-M S, R JM, Mdld TL, Bw ML. pv lul fld lss d QSAR subss bd h P4 2D6. B Md h 23;11:44.. H N, Zh W-Q, Shkl D, Edk T. Ihb ffs f H1-hss YP2D6- d YP29-dd du bl s hu lv ss. Eu J l Phl 22; 7: Rbs RL, B EJ, J PR, Kd MA. Hw h phs f h P4 s ff psb. N Z Md J 22;1: B K, Abh. G plphs f YP2D6. Id J Phl 21;33: Js BP, Vll-B J, B EJ. Quf f l d l hu pls b lqud hph-d ss sp L-MSMS). J h B Al Thl Bd Lf S 211;879: Ekbush TH, Mudks EN. Th p f DNA hls h uus supls fldd-fb ds d ds. ll 1978; 13: Mll SA, Dks DD, Plsk HF. A spl sl u pdu f x DNA f hu uld lls. Nul Ads Rs 1988;16: Rbs RL, Kd MA. Rpd d f h P4 2D6 llls uss. l h A 26;366:34831.
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