Mar 1, 2010 - liver UDP-glucuronosyltransferases (UGTs) to form an inac- tive B-glucuronic acid derivative, ... may be mediated by several different families of enzymes, including ... anion transporting polypeptide 1B1 (OATP2, OATP-C, LST-1). these factors ..... clearance, and UGTi A1*28 genotype are statistically signifi-.
,ο
Oぃ、201Q島 209-217
)sition and Toxicity:A Review
′ α″,α θろ Sα ブ ″Cθ ttP′ ι力 sブ ッιCa″ εθ″C`″ ′ 多 ια′Ccκ 女 aグ ブ `れ
ε ω,駒 ′ ブ ι α ′ 乱″κ ttα θ ι γ ′ rr772ι ′ α κ /bψ α げP力 α
'8,″ Иe″ ′力75,E｀ 3∂ fθ
D‐
-367∂ ,しIS4
lccr drug, cspccially for thc tteatment of C010rectal canccr 、 civ誠 lon to thc activc mctabolitc SN-38.Patients trcatcd with delaycd diarrhca,and the occurrcncc ofthcse advcrse rcactio,s
iics havc dcmonstratcd a rclationship bchvcen SN-38 phama― cnetic polymorphisms in UDP― giucuronosyltlansferasc(UGT) bccn linkcd to interindividual phallnacokinctic variability and encoding drug― mctabolizing enzymes or transportcrs that are tl rolc in thc pharlnacokinctic and pharlnacodynamic proflle of
inacogenctlcs ofirhotccan
netics,UGTlAl,variability
livcr cclls
◎ 2010 Bentham Science Publishers Ltd.
209
羮 Ftti″
Vο・3 210 C″ ″ι″′Crinた α′P″ α″″αεοO騨,2010,レ ♭I島 ノ
α″″Sp″ ″ ″ぅ 。 。 “
CPT-11 ４ヽ Ｍ
イ ダ 1籠
▼ 手 ｌｌ︱′ ヽ
崚 ︶¨ ゝ
SN-38
SN-38
SN-38G
HeparOc/e Re/7arrυ bυ lar ce〃
tttR躍 卿″ 朧胤 ‰蹴鋼犠l踏鍵 ilttl現 瀞 鸞 嚇絲鷺i輔 異 !驀
ti葛
:
節1爺軍乳Fま T 窯ittl∬認if:滋 l'お 燎慇点 驚 縫ltte棚 轟般 ぶ 器,響遣搬ぶ厳器:」 )躙セ
anlon transpo五 ngpottepidelB1
0ATP2,OATP C,LST-1) and
tllese factors, inherited factors causing differences in
Gilbert's
syndromc
who
Were
homozygous for
υG″ Иf*28[22,23]led tO mOre detailed hvcsagations.
pharmacokilletic properties(pharmacOgenetics),in pttticular
drug metabolism[14],are nOW knowη to bC associatcd
r=な 樹:跳 ∬C群 翼
with tlle efflcacy and totticity of several anticancer drugs,
≒ 器:Ъ tt」 羅 :inユ よ 盤肝
interindividual differcnces in irinotecan pharlnacokinetics and toxicity.
Scveral lines of evidcncc have linkedび ('rfИ f*2∂
geno‐
聾 爵驀驚鸞奮
UCI■Ar'2∂ and lrinotecan ToxiCity lnterhdividual variability in tlle phttmacokinedcs(glu―
tth雰 SN-38 κ d“ ⑪」 側 Ю 五 慧 讐朧 盤鵬 :: is considered one of the ma0 亀 scvere toxicity[15-17].InvCStigators have thus focused pri―
I湖攀 聯蠅l椰聯 1儡悧驀 notecall.Dccreased bil血
bin― glucuronidation
Capaciサ
of
UGTlAl is clearly seen in patients with Gilbert's syndrome, for which the genetic basis has been establiShed fllttp:〃 galiela.pha.ulaval.c″ allelesノυGTlA/UGTlAl.html.Gilbert's
syndromc is most
assOCiated wil■ homozygosity for tl■ e(TA)7 allele σ″ И′(し「GttИ f*2∂ ), m the proximal promoter region ofし 石
commonサ
causing reduced gene and protein expression of UGTlAl [18,19].Previous sttdies have thus investigated the relation¨
σ″ Иf*2∂ genotype status alld the extent of ships betweenし Д SN-38 glucuronidation and/or thc severity of irinotecan― related toxicity.Highly/variめ le UGTlAl expression caused byしr(,71/1*2∂ results in up to 50-fold interpatient vttriabil―
ity in the rate of SN-38 glucuronidation[20,21].CaSe re_ ports of iinotecalt toxiciw in patients with colorectal cancer
壼
Prrα
″αcοgι ″ Jcs ′
arfrir。
`′
Vο .3 211 ″たα′Praα ′ ″αι O′ 0駒ぅ 201Qレbl島 ノ σ″″″ ″rC′′
″α″″rottJク ″ ″DJッ ο s″ ο “
Obtained froln these combination studies generany repliCated tlle indings of single― agellt allalyses.Collect市 eし ,theSe vere considered to provide compelling cvi― ObserVations 、 rcttИ f*2∂ genowpe is associated widl toxicity dellCe thatし based regimcns. (neuttOpellio ofirinOtccan―
In response to the above indings,the FE)A tookい Ⅳo
ac―
10ns in 2005.Fttst,the package inscrt was revised to statc rG7′ И′*2∂ that individuals who are homozygous for tlteし
smaller trials,and no dose reduction、 vas re9ommended by tl■
ese authors for patients wi■ the C/1C″ /f*2∂
genotype
ln general,the impaCt Of a given gcnetic polymorphism on tlle phenotypic response to a drug dtters among distinct ethnic populations because of the disparatc distribution of
polymorphisms.A polymorphism that is an七 理 ortant deter_ nlinallt ofthe phenotypic response to a drug in a given el■
lic
group may not be detected in otller populations. The com―
allele are at hcreased ttsk for neutropenia after starthg iri―
plex genetic basis ofUGTlAl activiり preCludes direct com―
■Otecan treatment, and tl■ at a reduced initial dose should
parisons of irinotecan― related toxicity among different etllnic
tllerefore be considered for such patients Second,the FDA
groups;for examplc,tlle samc gcnetic variant(s)might have differettt effects on irinotecan toxic■
霧:撃 ℃ き孔 掟予乱 出
:LIttχ
搬
鑑
L』 ::
InC,Madison,WI)It iS importttt to lndicate,however,that dosage reconllnendations for patients cattγ ingい″o copies of 「(フ r′ И′*2∂ allele had not yet been establishcd. Based the し
.[25]rccommended a On their own allalyses,Imlocenti`′ α′ 20シ 6 dOSe reduction on tl■ c basis of the area under the tiine―
cOncelltration curve(AUC)for SN… 38.Bccause undelteat― ment Can lead to poor outcomes,tlle problem of dose ad¨ justments must be addrcssedprospectiveけ .[29]have retrospect市 ely exam― Recentけ ,Kweckel θ′α′ *2∂ gcnotype and(i) incd the associations betweenし 「G″ И′ response ratcs,(il)fCbrile neutropcnia and(lil)dOSe htensiり in patientsヽ ″ith inetastatic colorectal canccr treated witll iri― ■otecan.υ G7′ И′*2∂ genowpc waS deterlnined in 218 pa― iellts receiving irmotecan(eitller irst― line therapy witll capecitabhe or sccond― line as monotherapy)for metastatic
colorectal cancer.(TA)7 homozygotes recc市 ing innotecan conlbination therapy had a higher incidcnce of febrilc neu― 廿openia(18.2%)compared to tl■ e otllcr genoり pes((TA)6/
(TA)6:1.5%;(TA)6/(TA)7:6.5%,P=0031),雛ld
tllese mli―
viduals receivhg廿 hotecall monotherapy also suffered from more febrile neutropenia(19.40/0)cOntpttcd to pttients with
tlle(TA)6/(TA)6 genoサ pe(2.2%;P=0015).RespOnse rates alnong genoサpes were not different for botll regimens,alld (TA)7 homozygotcs did not reccive a low∝ mcdian ttinote― call dose,number of cycles(P>025)or more frequent dose redtlctions colmpared to thc otller genoサ pcs(P>0.45).Re―
ductiOns in dose werc maね け owing tO tlne occurrcnce of dittrllea,not(febrile)neuttOpenia Thus,(TA)7/(TA)7 carri― ers have on averagc a higher chance of febrile ncutropenia fol10whg rinotecall treatntcnt,but are able to receive silnilar
dose and number of cycles compared to other genoり pes.It should be pointed out tl■ at,until mOre prospective data ale
avttlable,
the opumal dosage for patients 、 vith tlac げG7′ И」*2∂ genotype remains unclear. Several phasc I dmical ttials to prospecdvely de“ rmine an optimal irinote― Can dose in patients homozygous lor υGrf/1*2∂ are cur― rently ongoing[30]. After the revision of the package insert of rinotecan, SOme prospect市 e[31,32]and retrOspect市 e[33,34]studies further sho、 ved the relation beか ″een UGrfノ 4f*2∂ and iri¨ ■ Otecan― related toxicity Toffoll α α′ .[35]conduCted a large prOspective study witl1 250 metastatic colorectal cancer pa―
ients icated witll FOLFIRI and and also concluded that υcrfИ 」*2∂ is of somc relevance to irinotecan‐ induced tox―
;hOWever,し rCr′ Иf*2∂ appears to be somewhat less inlpOrtant than previousサ thOught on the basis of results in
iCiサ
y in distinct etllnic
「(,rfИ f*28 is groups Moreover, thc anele frequency of し
several thes higher in whites(03 to O.4)tllall in Asians (∼ 0.15)[36,37]. υGrr/1*6
AND IRINOTECAN TOXICITY
In addition to υσ″ Иf*2∂ ,other υCttИ ′ gene poけ ― morphisms have been shown to influence functional activity and be associated with Gilbert's syndrome or drug toxicity (http://WWЪ v.galien.pha ulaval.ca/alleles/UGTlA/LIGTlAl.h ml)MiSSense polymorphisms in exon l and in tl■ e shared
exons 2 to 5 have been described.Of particular relevancc to
East Asian populations is a mutration in exon l(21lG>A, *6[18,38-40].ThiS lllutation G711り ,referred to as υGrfИ ′
reduces cataサ tic aCt市 ity by 60%in homo2γ gotcs[41,42]. Interestillgly,tllis functional pollrmorphism is not found in whites[18,38-40].The hOmOろ /gouS presence of UGr′ Иf*σ signiflcalatly inttars gl・ lcuronidation
of SN-38[43],but Was
not rclated to irinotecan to対 ciり in One study[24]In con― 廿ast,a striking association、 vith higher toxiciv waS fOund in Korean patients treated v/ith irinotecan and cisplatin for ad― vallccd nonsmall‐ cell lung cancer[44].The relatiOn be“ een びGrfИ ′*6 and irinotccan― mduced toxiciサ Was also obser―
bed in Chmese patients[45]About 2.5 to 4.6%of the Japa― nese population is estimated to catt at least one each of the びGrfИ f*6 andし「Crf∠ f*2∂ alleles[39,42,46],whiCh fre_ quency is silnilar to or slightly higher than the pcrcentage of individuals wllo are homozygous forし r(,r′ И′*2∂ .The coex― И′*6 andし rCrfИ f*2∂ in Japanese patients istcnce of UGτ ′ with ca12cer apparentlD7 1ow∝ s the SN-38 glucuronidase ac― t市 ity
of UGTlAl,and rcsults in a phenowpic effect similar to tllat obsen/ed h homozygotes forし rc″ И′ワ ∂ [47].In― υG″ Иf*6 or deed, patients witll haplotypes harbormg
「cr′И′*28 had signiicantly reduced SN-38G to SN-38 し AUC ratios,with the effects ofし rcη И′*6 orび Gη /1*2ε being of a similar scale.A gene dose effect on tllis ratio、 vas obseⅣ ed for the llumber of haplotypes contammgし rc7И fワ ∂ or υGttИ ′*6(5.55,3.62,alld 2.07 for O,1,and 2 haplo― types,respecively,P
