(1)...109 (2)...110 (1) 28...111 (2) 28...113 (1) Seg...115 (2) Seg...117 (3) Seg...119 (4) Seg...120 (1)...122 (2)...122 (3) ( )...126 (1) (PCA)...127 (2) Draize...128 (1) Ames...129 2 in vitro...132 3 in vivo...135 (1)...137 (2)...138
2-AA 9-AC ALP EMS DNCB ENNG OTC LD 50 NF 20-MC CPA MNPCE MCH MCHC PCE S.D. S.E. 2-9- 2 4- -1- N- -N - -N- ( ) 50% 2-20- Micronucleated Polychromatic Erythrocytes Mean Corpuscular Hemoglobin Mean Corpuscular Hemoglobin Concentration Polychromatic Erythrocytes ( ) ( ) (+)-(S)-4-[1-(2,3-dimethylphenyl)ethyl]-1 H-imidazole monohydrochloride JAN dexmedetomidine hydrochloride (DEX) INN dexmedetomidine (R)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-i midazole
-1 (g/kg/) (g/kg/) 0.1 1 5 10 20 : 5 mg/kg mg/kg : 10 mg/kg 0.1 1 5 10 20 : 5 mg/kg mg/kg : 5 mg/kg : 2 mg/kg 0.5 1 2 mg/kg : >2 mg/kg GLP ( ) -1 ( ) -2-3 ( ) -4-5 ( ) : <10 10 40 160-6 28 : <10 ( ) : <10 10 50 250-7 28 : <10 ( ) 10 6 Seg (2 ) 6 18 54 54-8 2 6 ( ) 21 2 2 20 200 20-9 615 20 ( ) Seg <6 6 24 96 96-10 618 96 ( ) Seg 16 2 8 32 8 2-11 25 2 ( ) 8 16 (72 168 ) g/kg/infusion 8 16-12 ( ) ( ) 0.0625 0.25 1 ( ) g/kg/infusion 1.0 mg/animal -13 (6 ) ( ) 50g/animal -14 (10 ) ( ) 106
51500 g/plate ( ) Ames Test 15000 g/plate ( ) 10200 g/ml ( ) GLP ( ) 11.7100 g/ml S9 mix 50350 g/ml -18 ( ) in vitro 12.5168 g/ml -19 S9 mix 100488 g/ml ( ) 40 100 250-20 g/kg ( ) NMRI 5.0 mg/kg ( ) -1 in vivo 1.25 2.5 5.0 CD-1-21 mg/kg ( ) 1003000 1000g/mL -22 g/ml ( ) 1.253000 200g/mL in vitro -23 g/ml ( ) 28 400 2000 g/kg/ -15-16 -17 : 400 : 400 g/kg/ ( ) -24 5 mg/kg 2 mg/kg 1 mg/kg 28 10160g/kg/ 10g/kg/ 28 10250g/kg/ 250g/kg/ 10g/kg/ 107
18g/kg/ 54g/kg/ 6g/kg/ 200g/kg/ 20g/kg/ 96g/kg/ 96g/kg/ 8g/kg/ 2g/kg/ ( ) Ames 5 mg/kg NMRI GLP CD-1 GLP 5 mg/kg L 28 PR 400 g/kg/ 108
0.120 mg/kg 14-2 5 mg/kg 10 5 mg/kg 3 4 1 1 1 NMRI 30 g 0.1 1 5 10 20 mg/kg 5 5 mg/kg 5 mg/kg : 1 5 10 mg/kg 10 mg/kg : 1 20 mg/kg : 1 SD 7 0.1 1 5 10 20 mg/kg 5 5 mg/kg 5 5 mg/kg 5 mg/kg : 4 10 mg/kg : 5 20 mg/kg : 5 5 mg/kg : 4 10 mg/kg : 4 20 mg/kg : 5 109
1 0.5 1.0 2.0 mg/kg 14 ( -3) 2.0 mg/kg 1 1 ( ) 0.5 1.0 mg/kg 2.0 mg/kg 3 0.5 mg/kg 2.0 mg/kg 0.5 1.0 mg/kg 2.0 mg/kg 1015kg 0.5.0 2.0mg/kg 0.1mL/kg 14 0.5mg/kg 1.0mg/kg 2.0mg/kg 1 1 1 1 0 0 0 0 0 ( ) () ( ) ( ) () ( ) ( ) ( ) 2 mg/kg 110
1 10 SD 0 10 40 160g/kg/ 1 1 28-4 10g/kg/ 160g/kg/ 40g/kg/ 28 2 160g/kg/ 160g/kg/ 160g/kg/ MCH MCHC 10 g/kg/ 40g/kg/ ALP 160g/kg/ PT PTT 40g/kg/ 1) 40g/kg/ 160g/kg/ ALP ALP ALP 2 2) 160g/kg/ 40g/kg/ 3)-5) 111
10g/kg/ 10 /kg/ SD 6 180 g 150 g 1 ml/kg 1 1 28 (g/kg/) 10 40 160 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 RBC Hb Ht Ht MCH MCHC Na + ALP ALP K +, Mg +, Na + ph ph ph ( ) ( ) ( ( ) ) <10g/kg/ Bonferonni t 1) Kaheinen, P.: Research Report 5.7.1989, Farmos Group Ltd., Research Center 2) Hirsimaki, P. et al: Research Report 6.2. 1989, Farmos Group Ltd., Research Center 3) Kamibayashi, T. et al:anesthesiology 93: 1345-1349 (2000) 4) Bloor, B.C. et al: Anesthesiology 77:1134-1142 (1992) 5) Schmeling W.T. et al: Anesthesiology 75: 499-511 (1991) 112
3 0 10 50 250g/ 1 1 28-5 10g/kg/ 250g/kg/ 50g/kg/ 50g/kg/ 250g/kg/ 10 ( ) 250g/kg/ 6 5 50g/kg/ OTC( ) 250g/kg/ GPT OTC GPT 1) 2),3) 50g/kg/ PAS (Intracytoplasmic eosinophilic inclusion bodies) 250g/kg/ 1 PAS 4)-7) 113
10g/kg/ 10g/kg/ 2325 8.911.0kg 2425 8.011.2kg 0.25 ml/kg 1 1 28 (g/kg/) 10 50 250 3 3 3 3 3 3 3 3 0 0 0 0 0 0 0 0 OTC OTC GPT ph ph * 10g/kg/ * OTC(Ornithine Transcarbamylase) 1) Amacher, D.E. et al: Food Chem Toxcol 36: 831-839 (1998) 2) Sanhouri, A.A. et al: Br Vet. J. 146: 36-42 (1990) 3) Yannai, S. et al: Arch Toxicol 54: 145-156 (1983) 4) Ghadially, F.N.: Fourth Ed., Boston: Butterworth-Heinemann, pp. 442-443, 544-551 (1997) 5) Wills, E.J.: Ultrastructural Pathology 16:491-503 (1992) 6) Biava, C. et al: Am J Pathol 46:775-787 (1965) 7) Murti, G.S. et al: Am J Vet Res 26:63-67 (1965) 114
24 SD 0 6 18 54g/kg/ 10 71 2-6 6g/kg/ 54 / 18g/kg/ 18g/kg/ 6 g/kg/ 18 54g/kg/ 18g/kg/ 20 18g/kg/ 54g/kg/ 2 1), 2) 54g/kg/ 1 1 18g/kg/ 2 3) F1 18g/kg/ (F0) 18g/kg/ 6g/kg/ 54g/kg/ (F1) 18g/kg/ 6g/kg/ 1)Magness, R.R. et al : Am. J. Obstet. Gynecol. 155 897-904, 1986. 2)Eisenach, J.C. et al : Am. J. Obstet. Gynecol. 160(2) 471-476, 1989. 3)Akatuka, K. et al : J. Toxicol. Sci.(Suppl 2)123-139 1972. 115
) SD 6~7 210 g 10~11 215 g 1 ml/kg 10 2 1 1 g/kg/ 0 6 18 54 24 24 24 24 24 24 24 24 0 0 0 0 0 0 0 0 - - - - - - (%) 2) 100 (24/24) 91.7 (22/24) 100 (24/24) 100 (24/24) (%) 2) 100 (24/24) 81.8 (18/22) 95.8 (23/24) 95.8 (23/24) - - 12 10 10 11 1,3,4) 14.42.0 13.71.6 13.42.3 14.51.9 1,3,4) 13.32.2 12.62.6 12.62.3 13.82.7 (%) 9.0 9.5 6.7 6.9 1,2,4) 1.32.3 1.31.9 0.91.1 1.01.0 (%) 6.9 6.3 11.1 7.2 1,2,4) 0.831.19 0.700.82 1.201.55 0.600.80 1,2,4) 0.080.29 0.100.32 0.200.63 0.501.20 1,3,4) 12.32.5 11.82.3 11.22.7 12.82.2 ( ) 1.0 1.0 0.81 0.86 (g) 3,4) 3.590.22 3.420.26 3.130.28** 2.590.44*** - - - - - - - - (100 ) (79 ) (77 ) (97 ) 1 7 8 14 29 2 9 10 14 31 3 9 11 15 35 4 10 14 14 32 5 25 28 27 54 6 6 8 19 81 18 21 27 86 1 2 6 40 1 7 2 8 12 8 13 12 (%) 100 (12/12) 100 (8/8) 100 (13/13) 91.7 (11/12) () 4) 21.90.5 21.60.5 22.10.8 22.10.3, 12.63.9 13.31.3 12.22.0 12.02.4, 11.84.0 12.81.2 9.62.7 9.33.4, 1.01.2 0.40.5 2.63.3** 2.72.8*** 4 97.7 100 97.6 95.5 (%) 12 94.6 97.1 96.0 93.8 (%) 96.8 97.1 98.3 98.1 1 6.60.4 6.30.4 6.10.5* 5.10.4*** (g) 4) 4 10.30.6 9.40.7 9.41.2 7.90.7*** 47.93.3 45.05.1 47.94.7 40.73.4*** - - - - - - - - - - - - - - - - - - - - - - - 10 9 13 13 (%) 90 (9/10) 100 (9/9) 100 (13/13) 92.3 (12/13) 1,3,4 12.23.8 13.11.4 12.82.1 10.13.3 (%) 1,3,4) 10.92.9 12.02.4 11.52.1 8.72.9 F 2 4 (%) 2) 100 99.1 96.7 96.6 - - - - (g) 4) 1 6.90.6 6.50.6 7.00.5 7.40.7 4 10.91.3 10.01.2 10.91.1 11.31.3 1.58 0.95 0.85 1.07 6g/kg/ 54g/kg/ 6g/kg/ (1) 1 2) Fisher 3)Bonferonni t 4) S.D. * p<0.05 ** p<0.01 *** p<0.001 116
25 SD 0 2 20 200g/kg/ 1 1 615-7 2g/ / 200 g/kg/ 20g/kg/ 200g/kg/ 2 8 9 20g/kg/ 200g/kg/ 20 200 g/kg/ Seg 2 20g/kg/ 2g/kg/ 200g/kg/ 20g/kg/ 200g/kg/ 20g/kg/ 117
SD 3 ( ) 250300 g 1 ml/kg 615 1 1 (g/kg/) 2 20 200 25 25 25 25 25 23 21 22 0 0 0 2 1) 1,3,4) 14.13.2 14.13.1 14.02.5 13.81.7 1,3,4) 11.83.6 12.32.2 12.93.0 13.31.9 2,3,4) 2.33.3 1.72.1 1.11.9 0.61.7 (% 4.5 6.0 4.8 26.7*** 2,3,4) 0.50.7 0.70.8 0.60.7 3.63.4** 2,3,4) 0 0 0 0 1) 0 0 0 0 )1) 274 267 257 195*** (g) 1,4) 3.70.6 3.80.7 3.40.6 2.20.4*** (g) 1,4) 0.510.08 0.500.04 0.480.06 0.350.06*** ( ) 1) 1.01 0.95 1.01 1.14 182 186 172 133 11.1 2.2 2.3 7.5 2 0 0 0.6 26.3 3 4.9 4.3 10.5 76.7 4 23.6 12.4 35.5 93.2 5 0.5 0.5 2.9 54.9 6 0.5 0 0 12.0 7 0 0 0 9.8 8 0 0 0 18.0 2g/kg/ 20g/kg/ 20g/kg/ 1) Bonferroni t 2) 2 Fisher 3) * p< 0.05,** p< 0.01, *** p< 0.001 4) S.D. 118
12 Himalayan 0 16 24 96g/kg/ 6 18 1 1-8 7 20 6g/kg/ 60 24g/kg/ 60 96 g/kg/ 24g/kg/ 29 2 24g/kg/ 1 1 2 96g/kg/ 6g/kg/ 6g/kg/ 96g/kg/ 96g/kg/ Himalayan 78 2.462.88 kg ml/kg 618 1 1 6 24 96g/kg (g/kg/) 6 24 96 12 12 12 12 0 0 0 0 1) 1,3,4) 8.61.4 9.11.4 9.01.0 8.51.9 1,3,4) 6.61.3 7.02.1 6.53.0 6.82.3 () 2) 23.3 22.9 27.8 20.6 1 1 % 16.5 7.1 20.5 11.1 2,3,4) 1.12.4 0.91.5 1.31.9 0.80.9 1) 0 0 0 0 0-6hr 2 2 2 3 7-24hr 3 3 4 1 1) 66 78 62 72 (g) 1,4) 36.66.2 34.35.6 38.55.6 38.56.2 (g) 1,4) 5.030.80 4.560.91 5.341.25 5.451.31 ( ) 2) 1.44 0.89 1.08 1.13 (%) 3.0 1.3 0 1.4 <6g/kg/ 96g/kg/ 96g/kg/ 1)t 2)Fisher 3)1 4) S.D. 119
1 22 SD 0 2 8 32g/kg/ 16 25 1 1-9 Seg Seg 2g/kg/ 32g/kg/ 8g/kg/ 8g/kg/ 32g/kg/ 16g/kg/ 4 32 g/kg/ 8g/kg/ 7 (16 ) 32g/kg/ 2 32g/kg/ 20 32g/kg/ 8g/kg/ 2g/kg/ 120
1.31.5 1.21.1 1.62.0 2.22.6 SD 12 190~240 g 1 ml/kg 16 1 1 g/kg/ 2 8 32 22 22 22 22 0 0 0 0 - - - 7) 21.40.5 21.50.5 21.50.5 21.30.5 (%) 100 (22/22) 95.5 (21/22) 100 (22/22) 100 (21/21) 4) 1,3,7) 142 142 142 123 - - - - (%) 2 91.4 89.3 88.6 94.2 1,3,7) 1 12.82.0 12.52.5 12.42.8 11.32.6 - - - - 2 1 1.07 0.89 1.27 1.00 4 (%) 2 93 98 98 99 1 6.60.4 6.60.6 6.30.5 5.70.5 4 10.00.9 9.81.1 9.30.9 8.70.9 (g) 7 16.11.4 15.61.7 14.61.1 13.71.2 5 - - - 25 ( ) 79.03.7 77.14.8 73.83.5 69.53.6 - - - - - - - - - - - - - - - - - - 6) - - - - - - - - (%) 100 (21/21) 100 (21/21) 100 (21/21) 100 (21/21) (%) 95.2 (20/21) 100 (21/21) 100 (21/21) 90.5 (19/21) 1,3,7) 15.32.2 15.32.4 15.12.7 14.62.8 1,3,7) 14.32.3 14.22.8 13.82.3 12.42.3 1,3,7) - - - - 1,3,7) 0.40.7 0.61.0 0.40.6 0.90.9 1,3,7) 13.92.6 13.62.9 13.42.4 11.52.5 F 2 (g) 7) 3.660.28 3.770.32 3.730.22 3.780.27 (g) 7) 0.480.07 0.490.05 0.490.04 0.500.05 - - - - 8g/kg/ 2g/kg/ 2g/kg/ 1) t 2) 2 Fisher 3) 1 4) 1 5) 6) 7) S.D. * p<0.05 ** p<0.01 *** p<0.001 121
6 0.06258g/kg 416g/kg 6 0.0625 1g/kg 0.25g/kg 4g/kg 8g/kg 4g/kg 8 16g/kg SD 116g/kg 1 4 4 8g/kg SD 8 16g/kg/ 4 mg/kg/ 1 3 72 7 (168 ) 2 ml/kg/ 3 30 1 mg/kg 1 7 7 1) -1 0 18.3 16g/kg 122
20 15 10 5 0 p0.05, (Mann-Whitney U ) 7-2 5 16g/kg ( -10) 20 15 10 5 0-5 -10 1hr 5hr 1 2 3 4 5 6 7 p0.05 (Dunnett ) 123
No. 1hr 5hr 1 2 3 4 5 6 7 S702 S705 S777 2mL/kg/infusion S786 S789 S793 L776 L779 L780 L790 8g/kg/infusion L791 L796 H701 H769 H782 16g/kg/infusion H783 H784 H785 P700 P767 P770 4mg/kg/infusion P792 P794 P797 : : ++ : ++ 124
6 ( 713 4.75.4kg) 3 mg/kg 1 1 2 1 2 2 6 mg/kg 1 2 8 2222.5 8 16g/kg (16 24 mg/kg) 2 Seevers (A) (B) (1) 25 50 50 75 75 1 (%)100 AB A 3 1 No. (%) 0.5 ml/kg 0.25 ml/kg 1377 29.4 1368 15.8 1409 0 8g/kg 1368 50.0 1350 29.6 16g/kg 1350 21.7 1377 58.3 16 mg/kg 24 mg/kg 1350 65.4 1409 75.0 1409 76.0 1368 78.3 1) 5 139-143 1979 2) Seevers, M.H. : J. Pharmacol. Exp. Ther. 56, 147-156, 1936 125
4 ( 713 5.17.0kg) 10 / 1 125 250 g/kg/ 30 / 29 3 0.0625 0.25 1g/kg 23 125 250g/kg 30 / 0.0625 0.25 g/kg/ 2 0.25g/kg g/kg 3 2 4 3 * (1 )** (2 )** (g/kg) 125 or 250 0.0625 0.25 1.0 0.25 or 1.0 No. 625 2 2 or 3 2 or 3 2 1357 30.00.0 1.10.1 1.00.4 28.93.0 113.35.4 1382 30.00.0 0.90.4 0.30.2 58.95.0 63.73.8 1392 30.00.0 3.00.8 10.42.2 22.95.1 17.62.8 1403 29.30.3 1.30.5 67.76.3 136.613.9 * 3 ** 1 No.1403 250g/kg (2 ) 0.25g/kg No.1392 3 126
PCA Draize Hartley ( 250350g 6 /) 2 ml(t 0 : ) 1.0 mg/2 ml/animal (T 1 : ) 1.0 mg/2 ml/animal (T 2 )1 3 2 (6 ) 2 16 64 256 0.1 ml (T 0 T 1 T 2 T 3 T 4 T 5 ) 45 T 3 T 5 0.1 mg /ml/animal T 4 1.0 mg/ml/animal 0.5% (T 4 ) (T 3 ) (T 5 ) T 0 T 1 1) 2) PCA / s.c. T 3 (0.1 mg/animal) 5) i.v. 06 (1.0 mg/animal) 3) s.c. T 4 (1.0 mg/animal) 6) i.v. 66 T 2 (1.0 mg/animal) 4) s.c. T 5 (0.1 mg/animal) 5) i.v. 06 1) 3 2 (6 ) 2) PCA 1/16 1/64 1/256 45 3) (0.5 mg/ml)2ml # 4) (0.5 mg/ml)2 ml # 5) (0.1 mg/ml)1 ml 6) (1.0 mg/ml)1 ml # 127
Hartley (362419 g 6~10 /) (T 0 : ) 0.05(w/v)DNCB(T 1 : ) 0.05 # (T 2 ) 1 3 (10 ) (1 0.1 ml/animal 29 0.2 ml/animal) 2 T 1 0.05DNCB T 0 T 2 0.05 0.1 ml 24 48 04 1 DNCB (T 1 ) 6 3 1 3 1 (T 0 T 2 ) ( -14) / No. T 0 T 1 T 2 / 0001 0 0 0003 0 0 0005 0 0 / 0007 0 0 DNCB /DNCB 0009 0 0 0011 0 0 1001 0.5 1.0 1003 0.25 0.5 1005 0 0.5 1007 0 1.0 1009 0 1.0 1011 0.25 1.25 2001 0 0 2003 0 0 2005 0 0 2007 0 0 2009 0 0 / 2011 0 0.5 2013 0 0 2015 0 0 2017 0 0 2019 0 0 1 (24 48 ) (24 48 ) 4 0/6 3/6 0/10 # 128
Ames in vitro in vivo TA1535 TA1537 T1538 TA98 TA100 55000g/ 5000g/ 15 50 150 500 1500g/ 5 15 50 150 500g/ 4 1500g/plate 1) 5 5g/plate 6 ( -15) 1500g/ 5 15 50 150 500g/ 5 1 4 2 1 2-15 WP2uvrA 1 3 10 30 100 300 1000 2000 5000g/ 11000 g/ 7 ( -16) 11000g/plate 1) OECD Guideline for testing of chemicals No. 471: Bacterial reverse mutation test 129
/ TA1535 TA1537 TA1538 TA98 TA100 (g/ ) 1 2 1 2 1 2 1 2 1 2 112.0 190.6 123.8 132.6 133.6 114.0 244.4 264.2 105 1046.4 12.3 S-9mix (-) S-9mix (+) 0 123.0 154.7 101.0 172.1 91.5 154.0 243.5 241.5 111 1099.1 13.9 5 146.8 160.6 111.5 256.6 9815.1 113 106 15 172.5 150.6 91.2 171.7 132.9 162.6 231.5 211.5 20.8 10.0 50 102.5 134.7 102.0 120.6 122.1 90.6 213.2 314.5 1193.5 1236.4 ENNG 150 113.5 171.5 93.2 171.5 103.5 91.2 304.0 235.0 1006.1 1113.5 500 112.0 155.0 104.9 154.0 92.5 113.2 162.1 200.6 976.0 9413.1 1500 IL 104.5 IL 142.0 81.5 115.0 IL IL IL IL 5.0 2509.1 341 18.1 3.0 353 46.5 335 25.5 9-AC 80.0 X X NF 2.0 139 1361.0 27.0 1.0 1154.5 1129.0 141.5 143.0 121.0 151.5 171.7 141.5 251.5 253.2 1056.8 1132.6 0 122.1 171.5 103.1 141.2 132.5 112.0 265.3 304.0 1241.5 1099.5 5 163.2 181.5 181.0 335.9 934.6 15 131.2 152.1 135.7 140.0 153.8 131.7 265.5 323.8 9419.0 1228.4 50 152.9 171.0 171.0 143.0 102.5 133.6 302.9 302.1 1261.0 1178.7 150 92.1 172.9 141.2 146.1 115.3 150.6 272.1 304.0 998.5 1149.0 102 115 500 152.6 151.5 124.7 152.3 113.0 154.5 122.1 265.5 13.6 16.6 2AA 1500 72.0 93.2 100.6 134.6 92.5 130.6 IL IL IL IL 2.0 299 2247.0 9911.6 1154.0 18.2 1.0 694 47.1 0.5 288 21.4 266 2849.2 25.1 276 12.9 881 32.0 S.D. N=3 ENNG N- -N - -N- 9-AC 9- NF 2-2AA 2- IL X 130
WP2uvrA / (g/ ) S-9mix (-) S-9mix (+) 31.78.5 1 30.75.0 3 25.31.5 10 23.37.0 30 22.79.0 100 15.02.6 300 20.35.5 1000 18.34.5 2000 2.32.1 5000 0 ENNG 10 1304.0115.6 29.76.0 1 29.39.0 3 23.06.6 10 25.314.6 30 25.03.5 100 26.01.7 300 20.78.1 1000 15.09.6 2000 3.32.5 5000 0 2AA 50 218.739.4 ENNG N- -N - -N- S.D. N=3 2AA 2-131
L5178Y TK+/-TK-/- L5178Y S-9mix 37 3 48 TK 1213 90% 200g/mL 10150g/mL S-9mix 2 S-9mix S-9mix 40g/mL 20200g /ml S-9mix 40g/mL 22237/10 6 cells 1) ( -17) (g/ml) () 1 2 () S-9mix () S-9mix () DMSO 100 78 100 112 10 87 82 40 103 100 80 81 81 76 111 150 63 54 33 108 200 24 71 22 120 EMS 2.5 63 557*** 67 726*** DMSO 100 106 100 106 10 81 120 20 95 112 40 49 139* 86 114 80 61 106 110 45 150 30 102 22 88 200 12 100 13 113 20-MC 500 45 559*** 39 460*** EMS 20-MC 20-10 cell *p0.05, ***p0.001 1) Mitchell I.deG. et al: Mutagenesis 5: 159-164 (1990) 132
18 32 S-9 mix 3 15 29 2 1 100 4070% 3 S-9mix (1 300g/mL 2 350g/mL 32 ) 0 6.25% ( -18) S-9mix -2-19 S-9mix S-9mix(-)EMS( ) S-9mix(+)CPA( ) (g/ml) 11.7 46.9 93.8 500 S-9mix g 0.5 0.5 0.0 2.0 35.0*** 18 () (%) g 0.5 0.5 0.0 2.0 35.0*** 1 + (g/ml) 100 200 300 10 S-9mix g 2.25 1.5 1.5 6.0* 20.0*** () (%) g 2.25 1.5 1.5 6.0* 20.5*** + (g/ml) 12.5 50 100 500 S-9mix g 1.25 0.5 0.5 0.5 10.0*** 18 () (%) g 1.25 0.5 0.5 0.5 10.0*** + (g/ml) 100 200 300 10 S-9mix g 0.5 0.0 0.0 1.5 13.5*** () (%) g 0.5 0.0 0.5 1.5 14.0*** 2 + (g/ml) 12.5 25 50 500 S-9mix g 2.25 1.5 2.5 3.5 10.5*** 32 () (%) g 2.5 1.5 2.5 3.5 10.5*** + (g/ml) 50 200 350 10 S-9mix g 1.5 3.0 2.0 4.5* 37.5*** () (%) g 1.75 4.0 2.5 4.5* 38.0*** + 100 (g) (+g) ***p0.001, *p0.05 133
S-9mix -18 S-9mix 1 168g/ml 488g/ml 3 19 2 75.0g/ml 19 3 400g/ml 3 19 C B1-19 S-9mix 3 1 S-9mix S-9mix (-) C S-9mix (+) B1 S-9mix () S-9mix () 19 S-9mix () 2 3 S-9mix () 100 * p0.05 (g/ml) 40.4 82.4 118 168 1.0 0.5 (%) 0.5 0.0 0.5 0.5 38.0* + (g/ml) 168 240 342 488 7.50 1.0 (%) 1.0 2.0 2.0 2.0 32.0* + (g/ml) 12.5 25.0 50.0 75.0 0.3 0.0 (%) 0.5 0.0 0.5 0.0 32.0* + (g/ml) 100 200 300 400 10 0.0 0.0 0.0 0.0 0.5 17.2* (%) + 134
NMRI 5 40 100 250g/kg 24 48 1000 PCE/NCE 2000 PCE PCE MNPCE 2 1 30 2 30 250g/kg -20 PCE/NCE MNPCE 250g /kg NMRI 5 mg/kg GLP -1 GLP -21 24 48 NMRI 8 3139 2734g 5 24 48 ( 24 ) 40( /kg) PCE/NCE MNPCE (%) PCE/NCE 135 100( /kg) 250( /kg) 40(mg/kg) 1.08 1.01 1.16 0.91 1.40 1.65 1.54 1.60 1.61 0.91 1.36 1.28 1.38 1.26 1.16 0.15 0.09 0.18 0.11 4.50** 0.15 0.15 0.14 0.19 3.33** 0.15 0.12 0.16 0.15 3.92** 1.20 1.09 1.21 1.24 1.64 1.47 1.42 1.51 1.42 1.28 1.32 1.37 0.16 0.12 0.10 0.13 MNPCE (%) 0.20 0.18 0.17 0.11 0.18 0.15 0.13 0.12 MNPCE(Micronucleated Polychromatic Erytrocytes) MNPCE(%)=MNPCE /PCE 100 **p0.01 1) O brien, H. et al: Br J Haematol 51: 451-456 (1982) 2) Asanami, S. et al.: Mutation Res. 393: 91-98 (1997)
CD-1 1.25 2.5 5.0 mg/kg 2 2030 28 5% 1ml 24 48-1 PCE/NEC MNPCE (%) 50 mg/kg 27 33 5 PCE/NECMNPCE (%) PCE/NEC MNPCE (%) CD-1 7-8 2734 1 5 24 48 1.25(m /kg) 2.5(m /kg) 5.0(m /kg) 50(mg/kg) PCE/NCE 0.81 0.89 1.05 1.23 0.57* MNPCE (%) 0.10 0.09 0.06 0.08 2.92** 24 PCE/NCE 0.93 0.92 0.91 0.99 MNPCE (%) 0.05 0.07 0.07 0.04 PCE/NCE 0.76 0.66 0.57* MNPCE (%) 0.08 0.12 3.11** 48 PCE/NCE 0.91 0.83 MNPCE (%) 0.08 0.04 MNPCE(Micronucleated Polychromatic Erytrocytes) MNPCE(%)=MNPCE /PCE 100 *p0.05, **p0.01 136
5 SD 1003000g/mL( 0.1mL) 5 20 mg/ml 5 2 3000g/mL 5 3 2 100 200g/mL 1000g/mL 1 10 SD 400g 1 5 (100 200 1000 3000g/ ml 0.1mL 5 20mg/mL 0.1mL 0.1mL (g/ml) 20mg/mL 100 200 1000 3000 5 5 5 5 5 5 137
1.253000g/mL in vitro ( ) ( ) 545 nm 100 200g/mL 3000g/mL 100% (0.3 1.5ng/mL*) *: DEX-97-028W97-249W97-245W97-246W99-302W98-273 J-DEX-99-001 5.0mL 100L 3760 545nm (g/ml) 1.25 2.5 5.0 10 20 100 200 3000.001.916.000.001.001.000.001.001.002.938 (%) 0 0 0 0 0 0 0.1 98.0 1 3 28 0 400 2000 10000g/kg/ 10000g/kg 3 2 10000g/kg 2000g/kg 1 PR 2 10000g/kg 2 10000g/kg 200010000g/kg 10000g/kg 400g/kg/ 138
56 6.58.7kg 56 6.08.0 g (1 :3 :3 ) 400, 2000, 10000g/kg/ 1 1 28 10000g/kg/ 3 2 (g/kg/) 400 2000 10000 3 3 3 3 3 3 3 3 0 0 0 0 0 0 0 0 1) 2) PR 1) 2) 2) 400g/kg/ 1) 2) 139