LCΠMSΠMS 法测定比格犬血浆中埃克替尼及其在药动学研究中的应用

1158 CN 3421206ΠR , ISSN 100922501E2mail :ccpt96 @21cn. com2008 Oct ;13 (10) :1158 - 1162LCΠMSΠMS 1 , 2 , 1 ,2 , 31,110016 ,; 2 ,201203 ; 3 ,310004 , : 2(LCΠMSΠMS) ,:32 ,4 ,(10 mgΠkg) (10 , 20 40 mgΠkg) LCΠMSΠMS ,:0. 510000 ngΠmL ,(RSD) 10 %AUC 0 - t(27. 3 15. 3) g mL - 1 hAUC 0 - t ( 7. 47 3. 30) ( 23. 5 11. 5) ( 54. 5 24. 9) g mL - 1 h ,27. 4 %: 2(LCΠMSΠMS) ,,, ;;LCΠMSΠMS ;: R969. 1: A : 100922501 (2008) 1021158205,,2008205228 2008210216 ,,,:,,,,,,:Tel : 021250800738 E2mail : dfzhongdf @mail. shcnc. ac. cn,( EGFR) , EGFR [1 - 5 ] (icotinib) , 42[ (32) ]26 ,722122242,, [6 ] (gefitinib) (erlotinib) ,, [7 - 10 ] 1 1. 1 ( 99. 9 %) ;(,99. 7 %) ;,;Sigma ;0. 5 %;1. 2 Thermo Finnigan TSQ Quan2tum Ultra ,( ESI ) Xcalibur 1. 4 ;LC210ADvp SIL2HT 1. 3 Zorbax XDB C 8 , 150 mm 4. 6 mm ,5m ,Agilent ;C 8 (4 mm© 1994-2009 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net

2008 Oct ;13 (10)1159 3. 0 mm I. D. ) ,Phenomenex ; 22(75 : 25 :0. 5 , VΠV ) ; 0. 5 mLΠmin ;20 L ;20 1. 4 ( ESI) ;3800 V ;320 ; (N 2 ) 35 Arb ;(N 2 ) 5 Arb ;(Ar) 1. 2 mTorr ; (MRM) ,(CE) 25 eV ; mΠz492. 2 mΠz 304. 1 () mΠz 256. 1 mΠz167. 0 () ;300 ms1. 5 100 L , 2( 40 : 60 , VΠV ) 100 L , (0. 04gΠmL ) 100 L 100 L ,1 min ,5 min ,5 min(10000 g) ,20 LLC2MS2MS1. 6 1. 6. 1 ,1250 mg ,250 mL ,25 mL24. 0 h 1. 0 mL ,,,, - 20 1. 6. 3 24 ,,812 kg3 , 12 h , 10 2040 mgΠkg ( 2 mLΠkg) , 0. 5 1. 0 2. 0 3. 0 4. 05. 0 6. 0 7. 0 8. 0 12. 0 24. 0 h 1. 0 mL ,,,, - 20 1. 6. 4 Topfit 2. 0 AUC 0 - t , t 1Π2= 0. 693 Πke ; C max , T max ;CLΠF = DΠAUC 0 - (D ) AUC 0 - t F2 DMSO ,5 %, 2. 1 ,5 mgΠmL ;, 1000 2000 4000 mg ,, ,mΠz 392. 1 mΠz 256. 1 ,0. 5 %200 mL , 5 10 20 mgΠmL [M + H] + ,1. 6. 2 8 , mΠz 304. 0,812 kg ,12 h , mΠz 166. 7 ,(1) 10 mgΠkg 2. 2 6 (2 mLΠkg) ,2 ,,10 20 40 min , 1. 0 2. 0 3. 0 5. 0 8. 0 12. 0 (2) 1 A :;B :© 1994-2009 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net

1160Chin J Clin Pharmacol Ther 2008 Oct ;13 (10)2 MRM A :;B :0. 5 ngΠmL 40 ngΠmL ;C:10 mgΠkg 3. 0 h ;I :,II :2. 3 ,,,100 L (1. 5 9000 ngΠmL) 100 L ,20 L ( n = 3) ;,,100 L ,20 L ( n = 3) ,,95. 0 % ,2. 4 100 L ,100 L ,0. 5 1. 5 5. 0 15 50 200500 1000 2000 5000 10000 ngΠmL ,2(40 :60 ,VΠV) 100 L , ( C) 1 ,( y) ,( w = 1Πc 2 ) ,y = 6. 65 10 - 4C + 2. 64 10 - 3 , r = 0. 99540. 510000 ngΠmL 0. 5 ngΠmL ,( RSD) 9. 6 % ; ( RE) 10. 0 %0. 5 ngΠmL 2. 5 100 L , 3 (1. 5 509000 ngΠmL) QC ,6 ,3 d ,,QC ,QC ,(1) (ngΠmL)RSD( %)RSD( %)RE( %)1. 5 1. 53 6. 0 8. 6 2. 050 53. 0 8. 9 5. 9 6. 09000 8700 7. 4 5. 9 - 3. 32. 6 3 ( 1. 5 509000 ngΠmL) ( n = 6) , ( 102. 0 8. 1) % (96. 7 2. 0) %(104. 4 0. 9) %(100. 4 2. 2) %3 2(RE 4. 2 %) ,- 20 30 d ( RE 2. 0 %) ,2 h(RE 4. 1 %) ,24 h(RE 8. 0 %) 2. 7 (10 mgΠkg) 2(3) : t 1Π2 (5. 6 2. 2) hAUC 0 - 24 ( 27. 3 15. 3) g h mL - 1 , AUC 0 - ( 27. 6 15. 4) g mL - 1 h , CL ( 574 © 1994-2009 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net

2008 Oct ;13 (10)1161548) mL kg - 1 h3 3 ( 10 mgΠkg) 2( x s , n = 8)10 20 40 mgΠkg 24: C max (1. 99 0. 56) (3. 88 1. 66) (6. 82 2. 40) gΠmL ; t max (1. 13 0. 58) (2. 00 1. 04) (2. 75 0. 89) h ; t 1Π2 ( 3. 09 1. 37 ) ( 2. 64 0. 77 ) ( 2. 17 0. 33) h ;AUC 0 - t ( 7. 47 3. 30) ( 23. 5 11. 5) (54. 5 24. 9) g h mL - 1 ;AUC 0 - ( 7. 49 3. 30 ) ( 23. 5 11. 5 ) ( 54. 5 24. 9) g mL - 1 h ; CLΠF ( 27. 1 13. 7 ) (16. 7 6. 43) (14. 6 6. 51) mL - 1 kg - 1 h ;10 mgΠkg 27. 4 %(20 mgΠkg) (40 mgΠkg) 43. 0 %49. 9 %,ESI ,,(N 2 ) (N 2 ) (CID) ,35 Arb ,5 Arb ,(CID) 25 eVESI2MS , ,,,,,,( T R = 3. 04 min) ( T R = 1. 5 min) ,AUC ,,AUC ,,,,: 4 ( 10 20 40 mgΠkg)2( x s , n = 8)[1 ] Wakeling AE , Guy SP , Woodburn JR , et al. ZD1839(Iressa) : an orally active inhibitor of epidermal growthfactor signaling with potential for cancer therapy[J ]. Can2cer Res , 2002 ,62 (20) :5749 - 5754.[2 ] Magne N , Fishel J , Dubreuil A , et al. Influence of epi2dermal growth factor receptor ( EGFR) , p53 and intrinsicMAP kinase pathway status of tumour cells on the antipro2liferative effect of ZD1839 (Iressa ) [J ]. Br J Cancer ,2002 ,86 (9) :1518 - 1523.[3 ] O Brien DP , Nelson LA , Williams JL , et al. Selectiveinhibition of the epidermal growth factor receptor impairsintestinal adaptation after small bowel resection [ J ]. J© 1994-2009 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net