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12.

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2000.
13.
14.
15.

bVKLT`ILV_[[jQòm14 CnY­700}XoX±ÖÌ AMS Ìpb

J. S. Fowler, N. D. Volkow et al, J. Nucl. Med., 40,

R c ê  C1) C  g ¹ ÷1) C ² ¡ F º2) C S i E2) C11541163, 1999.

_²Dü3)C¼ä²Y3)

A. M. J. Paans and W. Vaalburg, Curr. Pharm. Des., 6,1)OHEFt@[}®ïÐ15831591, 2000.

2)æê»wòi®ïÐ ò¨®Ô¤

M. Bergstrom, A. Grahnen and B. Langstrom, Eur. J.

3)®ïÐ

Á¬íªÍ¤

Clin. Pharmacol., 58, 357366, 2003.
1)

Í¶ßÉ

ßNC¢BÅÍíÌVòóâiÌ©çò¨®ÔwIÉæèÇ¢óâiðIð·é±ÆðÚIÆµ½qg}CN
h[WO±ÌKChC1) ª§è³ê½D»ÌªÍ è i Æ µ Ä AMS ( Accelerator Mass Spectrometry ) âPET(Positron Emission Tomography)ÈÇÌ´´xªÍ
@Ìpª§³êÄ¢é2)4)DÉ÷ÊÌ RI W¯ò¨ðp¢½qgPñ microdose ±ÍCqgÌò¨®ÔÉÖ·éf[^ªãòiJ­ÌúiKÅüèÅ«éæúIÈñÄÅéDò¨®ÔÉÍí·ª¶ÝµCbgCCkÌ¬ÑªqgÆêv·é±ÆÍÜêÅ

éDqgPñ microdose

±ÉÍbgCfbgª¶Ý·éªCqggDðp¢½ in vitro ±ÆÌZÉæèC]Üµ¢óâ»¨ð
Ið·é±ÆÍÂ\ÅFig. 1.

ë¤D¢¸êÉµÄà¤J­Ì

Plasma concentration­time profiles of total radioactivity measured by AMS or LSC in 4 male healthy volunteers after a single oral

administration of [14C]­Y­700 at a dose of 20 mg.

\27\

Fig. 2.

Relationship of plasma total radioactivity between AMS

and LSC measurement

Fig. 3.

Cumulative excretions of total radioactivity in urine meas­

ured by AMS or LSC in healthy male volunteers after a single oraladministration of [14C]­Y­700 at a dose of 20 mg
Each point represents mean and bars indicate S.D. (n4)æè¢iKÅqgÌà®Ôf[^ð¾é±ÆÍCò¨®
ÔÌí·ÉNö·éãòióâ»¨ÌJ­~ÌXN
ðñð·é±ÆªÅ«éÆÆàÉCR&D ÌXs[hAbvCRXg_EÉàqªéD
qgPñ microdose ±É¨¯éªÍ@ÌêÂÆµÄãqÌ@­ AMS ª§³êÄ¢éªC»ÌªÍ@ÌpáÉÂ¢ÄÍ\ªÈñÆÍ¢¦È¢D¡ñCñtr^ÌVKLT`ILV_[[jQòÆµÄJ­ÌY­7005)Ìqg}XoX±6) ÅÌæµ½÷CAC³¿ð100¿10,000{óßµ½ã AMS Åªèµ½DAMSªÍÅ¾çê½ªèlÆù¶Ì LSC ªÍÌªèlðär·
é±ÆÉæèCAMS @ÌLp«ÉÂ¢ÄØµ½D2)

±û@14C W¯ Y­700(ñ 3 MBqC85 mCi)ðí¬lj«É20mg Pñoû^µ½D÷CA¨æÑ³ð^ã168ÔFig. 4.

ÜÅoIÉÌæµ½De¶Ì¿14 C Êð LSC @Æ

LSC measurement

Relationship of urine total radioactivity between AMS andAMS @Åªèµ½DAMS @Í LSC @ÆärµÄ1,000{ÈãÌ´xðõ¦Ä¢é½ßCY¿ð100¿10,000{É´EhÆµÄCeí±Ò©çÌæµ½ pre­dose ¿Ì

Ü½ÍYÌ

VR14C Êðp¢½Dí±Ò No. 2 É¨¢ÄC120ÔÈ~uN¿Åóßµ½DÜ½CèÌÔÉ¨¯éÌ÷14 C ÊÌÔÏ»É·ðFß½D±Ì·ÍCLSC÷CA¨æÑ³ÌãÓ¨vt@Cð¢·é½ßC

@Å¾çê½lª»ÌèÊÀEtß©»êÈºÅúË\ÊÅñ0.3 Bq(ñ20 dpm)Ì¿ð HPLC ÉüµÉ¶¶½Æl¦çêéD÷¿É¨¯éèÊÀElÍ1.3 dpm/mL ÅÄCeæªðÌæµ½DSÄÌªè¿ÍOt@Cg»

ñªèµ½÷µ½ãCAMS ªèÉµ½D

é½ß
Á½D¡

14C ÊÌÀªlÍèÊÀElðå«­ãñÁÄ¨èC\ªÈªè´xðLµÄ¢éÆ»fµ½DAMS3)

Ê¨æÑl@@ Æ LSC @ Æ Ì Ô É  ¢  Ö « ð F ß ( X « 0.99, r 3­1)

÷Zx0.998)CAMS @ÍÉßÄ÷ÊÌ÷14C Êð¸xÇ­è ÷  ¿ ð 100¿1,000 { ó ß µ ½ ã C  ¿ 14 C Ê ðAMS ªèµ½D¾çê½÷úË\ZxÔÚ(nÊÅ«½(Fig. 2)D3­2)4)ÆÊrªèµ½ LSC ÌÊð Fig. 1 É¦µ½DobNO\28\Ar¦A¿ð100¿4,000{óßµ½ãC¿14C Êð AMS

Fig. 6.
Fig. 5.

Cumulative excretions of total radioactivity in feces meas­

Relationship of fecal total radioactivity between AMS andLSC measurement.

ured by AMS or LSC in healthy male volunteers after a single oraladministration of [14C]­Y­700 at a dose of 20 mg
Each point represents mean and bars indicate S.D. (n4)Fig. 7.

Typical HPLC­AMS chromatograms of plasma, urine, and feces in healthy male volunteers after a single oral administration of [14C]­Y­700 at a dose of 20 mg.

ªèµ½DÝÏAr¦(n4)¨æÑ AMS­LSC ÖðAMS ªèµ½DÝÏ³r¦(n4)Æ AMS­LSC Ö»ê¼ê Fig. 3 ¨æÑ Fig. 4 É¦µ½DÈ¨CobNOð»ê¼ê Fig. 5 ¨æÑ Fig. 6 É¦µ½DÈ¨CobNOEhÆµÄCeí±Ò©çÌæµ½ pre­dose ¿ÌVEhÆµÄCeí±Ò©çÌæµ½ pre­dose ¿Ì

R14 C Êðp¢½DAMS @Å¾çê½ÝÏAr¦Í

VR14C Êðp¢½DAMS @Å¾çê½³r¦Í LSC

LSC @Å¾çê½ÊÆêvµÄ¨èCÇDÈÖ«ð¦@Å¾çê½ÊÆÇ­êvµÄ¨èC÷¨æÑA¿µ½(X«0.929Cr0.997)DÆ¯lÉÇDÈÖ«ð¦µ½(X«0.969Cr0.997)D3­3)

3­4)

³r¦
³  ¿ ð 100¿10,000 { ó ß µ ½ ã C  ¿ 14 C Ê ð\29\ãÓ¨vt@C
í±Ò 1 ¼Ì÷(0¿2 Ô)CA(0¿168Ô)¨æÑ³

Table 1.

Relative percent of peak area of Y­700 and metabolites between HPLC­LSC and HPLC­AMS% in plasma% in urine% in feces

HPLC­LSCHPLC­AMSHPLC­LSCHPLC­AMSHPLC­LSCHPLC­AMS


95.3


99.8

15.5
80.4*

16.4
74.5*

29.0
67.7

23.0
72.4

M1Y­700*Y­700 glucuronide(0¿168Ô)¿ð HPLC(Ú®Ì¬¬F1 mL/min)Éñ

Adamkiewicz, Accelerator mass spectrometry (AMS):

20 dpm üµ½DúË\Ìo³êéÂ\«Ìá¢æªÍ

recent experience of its use in a clinical study and the»ÌÔÌnotðv[µCúË\ªo³êéÆ\ª³potential future of the technique, Xenobiotica, 31,êétßÍ 1 ª(1 mL)ÉªæµCeªæ¿Ì14C Êð AMS ªèµ½(HPLC­AMS)DÈ¨CobNOEh619632 (2001).
4)

G. Lappin and RC Garner, Big physics, small doses: theÆµÄCúË\ð HPLC ÉüµÈ¢êÌnotÌ14 C

use of AMS and PET in human microdosing of develop­

ÊðÊrªèµCeæªÌ14C Ê(0.002 dpm/mL Èº)ðp

ment drugs, Nature Reviews: Drug Discovery, 2,¢½Dnot14C Êð AMS ªèµÄ¾çê½ãÓ¨v
t @ C  ð Fig. 7 É ¦ µ ½ D Ü ½ C e s [ N (¢ Ï » Ì233240 (2003).
5)

I. Yamada, A. Fukunari, T. Osajima, M. Kamezawa, H.

Y­700¨æÑãÓ¨ M1)ªèßéð HPLC­LSC Å¾ç

Mori, and J. Iwane, Pharmacokinetics/Pharmacodynam­ê½f[^Æärµ½(Table 1)DHPLC­AMS ªèlÍC

ics of Y­700, a novel xanthine oxidase inhibitor, in rats

HPLC­LSC Å¾çê½lÆÙÚêvµ½DHPLC Æ AMSand human, Nucleoside, Nucleotides & Nucleic Acids,ð¹p·é±ÆÉæèCãÓ¨vt@Cð¾ç©É·8&9, 11231125 (2004).
I. Yamada, Mass balance study of [14C]­Y­700, a novel6)

é±Æªo½Dxanthine oxidase inhibitor, in rats, dogs, and human,4)

The 18th JSSX Meeting in Sapporo (2003).

_Y­700Ì}XoX±É¨¯é÷CA¨æÑ³¿úXN[jOÕ°±Ì@IEÏIâèðp¢Ä AMS @Æ LSC @ÌªèÊðär¢µ½DqgÌ÷CA¨æÑ³¿É¨¢ÄCAMS @Å¾çê
½ÊÍ100¿10,000{óßðsÈÁ½ÉàÖíç¸CLSC@Å¾çê½ÊÆ¢Ö«ð¦µC¶Ì¿ÌÉ÷
Ê14 C Êð¸xÇ­ªè·é±ÆªÂ\ÅÈwZp¶¾¤Á½DÜ½CI´çGq

HPLC @ÆgÝí¹Ägp·é±ÆÉæèCãÓ¨v
t@Cð¾ç©É·é±Æªo½DAMS @Í´xC
¸xÉ14 C ÊðèÊÂ\Å1)èCqgPñ microdose ±Ì¶Ì¿Ì14C ÊªèÉLpÅÍ¶ßÉ

2004N1119úàòÉÄJÃ³ê½uæ19ñú{ò¨®

éÆl¦éDÜ½CÔwïNïtH[Eúqg±Éü¯ÄEò¨®Ô^úË\Êª§À³ê½}XoX±Ì¿ªèÉ©çl¦évÉ¨¢ÄCMÒÍupÌ¤ÏR¸VX¨¢ÄàCAMS @ÌLøpªúÒ³êéDeÌüvÆ»óvÆÌèÅ­\µ½ªCtH[ÅÌc_ðÊ¶ÄCú{àÉ¨¢Äúqg±ÌÀ»»Ql¶£1)ÉKvsÂÈ@IEÏI__ª¾mÉÈÁ½DEMEA, Position paper on non­clinical safety studies tosupport

clinicaltrialswitha

singlemicrodose,

CPMP/SWP/2599/22, CPMP, London, 23 Jan (2003).
2)»±Å{eÅÍCtH[Ì­\àeÌTvð¦µ½ãCúÛèÆ³êÈªçÔÉ]TªÈ­\ªÉ¢cÅ«È©Á½__Éd_ðu«­W³¹é`ÅClðÎÛÆ

R. C. Garnner, Accelerator mass spectrometry in phar­·éúXN[jO±ÌÀ{ÉsÂÈ@IEÏ

maceutical research and development A new ultrasen­

I__¨æÑ§xIîÕÉÂ¢Äq×é±ÆÆ·éD

sitive analytical method for isotope measurement,3)È¨C{eÅÍCmicro dosing ±(MD ±)Ì½íÞ

Curr. Drug. Metab., 1, 205213 (2000).

©Ìµ§Èè`æèàL­C@IEÏIÏ_©çÌ¢

G. Young, W. Ellis, J. Ayrton, E. Hussey, and B.

ªßçêéÌæð¦·pêÆµÄCÊíÌæ I ±À\30\