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- かずまさ やまがた
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1 30mg 2
2 ...i... iii SIAD V In vitro...20 i
3 In vivo ii
4 AD APA APD 30 APTT antidiuretic hormone 30% AUC 0 24 AUC AUC camp C max C min CPM CYP2C8 CYP3A1 CYP3A2 CYP3A4 DDAVP DA GABA GLP ela PLC/UV PMC IC 50 i.v. Ki LC/MS/MS LSC PAS AUC 0 t AUC AUC t 0 AUC AUC 3, 5 - central pontine myelinolysis P450 2C8 P450 3A1 P450 3A2 P450 3A4 [deamino-cys 1, D-Arg 8 ]- 50% iii
5 p.o. PT SIAD S9 SD TK UGT V max syndrome of inappropriate secretion of antidiuretic hormone 9000 g Sprague-Dawley UDP-UDP-glucuronosyltransferase iv
6 JA PC PC-129 M1 5- PC M2 4,5- DM-3109 M3 4,5- DM-3111 M4 5- PC M5 5- PC M6 DM-3105 M7 SF M8 5- PC M9 DM-3112 M10 DM-3118 M11 DM-3119 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C l C 3 C 3 C C 3 v
7 M12 DM-3120 M13 - DM-3130 C 3 C 3 C 3 M14 DM-3153 M15 DM-3155 M16 DM-3157 M17 C 3 M-3 M18 M-4 M19 M-7 M20 M-8 M21 M-9 vi
8 R(+)- R(+)-PC (R)-(+)-PC S(-)- S(-)-PC (S)-(-)-PC R(+)-M1 R(+)-PC (R)-(+)-PC S(-)-M1 S(-)-PC (S)-(-)-PC (4R, 5S)-(+)-M2 (4R, 5S)-(+)-DM-3109 (4S, 5R)-(-)-M2 (4S, 5R)-(-)-DM-3109 (4S, 5S)-(+)-M3 (4S, 5S)-(+)-DM-3111 (4R, 5R)-(-)-M3 (4R, 5R)-(-)-DM-3111 R(+)-M4 R(+)-PC (R)-(+)-PC S(-)-M4 S(-)-PC (S)-(-)-PC R(+)-M5 R(+)-PC (R)-(+)-PC S(-)-M5 S(-)-PC (S)-(-)-PC C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 vii
9 2.4.1 in vitro in vivo M1M7 in vitro in vivo 1 2 in vitro in vivo M1M7 in vitro syndrome of inappropriate secretion of antidiuretic hormone 1
10 SIAD V 2 -V 2 - V 2 - V 2 -SIAD V 2 - in vitro in vivo camp V 2 - Verbalis 1 SIAD V [ 3 ]- V 2 - camp V 2 - V 2 - Ki nm V 2 -Ki nm V 2 -Ki nmv 2 - V 1a -V 1a - V 2-1/8 1/82 1/23 V 1b -V 1b - V 2 - ela V 2 - camp V mg/kg p.o.330 mg/kg p.o.330 mg/kg p.o. 2
11 2 3, SIAD SIAD SIAD V 2 -[deamino-cys 1, D-Arg 8 ]- DDAVP1 ng/h 110 meq/l 110 mg/kg 10 2 mg/kg 10 mg/kg 10 mg/kg central pontine myelinolysis CPM 7 4 CPM 5 SIAD 6 5 mg/kg 30 mg/kg CPM 10 mg/kg 30 meq/l 10 mg/kg V 2 - V 2 - V 2-7 8,9 V 2 - in vitro in vivo V 2 - ela V 2 - camp 3
12 V 2 - Brattleboro V V 1a - V 2-1/8V 1a - V 1a - IC µmv 1a - in vitro Ki 1.44 µm IC µm10 µm 56% V 2 -Ki 9.42 nm 1 mg/kg i.v. 10, M1M7 7 in vitro M1Ki 0.88 nm M2Ki 1.88 nmki 9.42 nm V 2 -M3Ki 6.59 nmm4ki 22.5 nm M5Ki 24.3 nm M6 M7 V 2 - V 2 - V R(+)- S(-)- M1M5 V 2 -S(-)- R(+)
13 S(-)- R(+)- in vivo M1M mg/kg p.o.300 mg/kg p.o mg/kg p.o. 6/ mg/kg p.o. 1/5 200 mg/kg p.o. 3/5 25 mg/kg p.o. 2/ mg/kg p.o. 4/ mg/kg p.o. GABA A GABA B 300 mg/kg p.o. 30 mg/kg p.o. 100 mg/kg p.o.300 mg/kg p.o. 30 mg/kg p.o. 100 mg/kg p.o mg/kg p.o. 30 mg/kg 0.23 µg/ml 30 mg 10 C max 4 ng/ml4 ng/ml * mg/kg p.o. 10 mg/kg i.v. 1 µm 5 *: 新薬承認情報提供時に置き換えた
14 10 µm mg/kg i.v mg/kg i.v. PQ ST T 10 mg/kg i.v.qrs QT 1 µm 30 µm 1 µm 10 µm APA V max APD 30 PQ QRS 200 mg/kg p.o mg/kg p.o. 3 mg/kg i.v.10 mg/kg i.v. 30 mg/kg p.o. 100 mg/kg 1000 mg/kg 30 mg/kg 30 mg/kg i.v M1M7 1 mg/kg i.v. 10 mg/kg i.v. M1 M2 10 mg/kg i.v. M15 10 mg/kg i.v. 10 mg/kg i.v. 6
15 30 mg/kg p.o. 10 mg/kg i.v. 0.3 mg/kg i.v. M3 10 mg/kg i.v M4M7 M5 0.3 mg/kg i.v.m4 1 mg/kg i.v.m6 3 mg/kg i.v.m2m3 M7 10 mg/kg i.v.m5 0.3 mg/kg i.v.m4 1 mg/kg i.v. M1 3 mg/kg i.v. M3M6 M7 10 mg/kg i.v. M5 1 mg/kg i.v.m6 3 mg/kg i.v. 10 mg/kg i.v.m7 10 mg/kg i.v. 0.3 mg/kg i.v.m4 M5 1 mg/kg i.v. T 3 mg/kg i.v. ST QRS M5 3 mg/kg i.v. PR QT 10 mg/kg i.v. M3 T PR QT M7 ST T C- 96% 1%PMC PLC/UV LC/MS/MS 20 C LSC mg/kg 7
16 3 mg/kg 30 mg/kg CYP2C CYP3A 12 3 mg/kg10 mg/kg110 mg/kg L/kg L/h/kg 14 C- 30 mg/kg 80% 80% 14 C- 30 mg/kg C max 2.3 C 24h C max AUC 4 M7 C max 4.5 AUC 24h C- 30 mg/kg C- in vitro µg/ml % % 14 C- 30 mg/kg 7782% 7992% % 2947% % % C- 30 mg/kg 8
17 14 14 C- 30 mg/kg AUC 72h µg eq.h/ml AUC 72h C- 30 mg/kg C- in vitro in vivo M1M21 in vitro in vivo M4 M5 5 - M8 M1 M1 M2 M3 M8 M11 M6 M7 M5 M17 M15 M
18 C 3 C 3 C 3 C 3 M5 C 3 C 3 M13 C 3 C 3 M4 C 3 M9 M17 M18 M15 M20 C 3 M8 M21 M19 C 3 M1 C 3 M11 C 3 M6 C 3 C 3 M10 M2 C 3 M7 C 3 C M16 C 3 C 3 M14 M3 M M2M
19 M7 AUC M4 M1M5M3 M7 AUC M6 M4M1M2 M19 M2M4M6M3 M7 AUC M6 AUC 2 AUC 2.4-1M % 74.62% 81.75% AUCng eq.h/ml 10 mg/kg 20 mg/kg 30mg/kg M1+M M2 (M14) a M M M M6+M11 b M M M M M M M M M M M M M a M14 b M6 M11 PLC M6 n= Table 2 M1M5 R(+)-S(-)- R/S M2 M3 (4R,5S)/(4S,5R)(4R,5R)/(4S,5S) R(+)- S(-)- R(+) S(-)- 11
20 mg/kg R/S M M M M M AUC t R/S M4 M7M2 M3 24 M7 M19M12 M6 24 M2M4 2 M %16.55% 9.29% 24 M4 M6M2 M9 48 M4 M6M12 M1 48 M6 M4M2M %26.42% 46.71% In vivo mg/kg mg/kg 30 mg/kg 100 mg/kg mg/kg mg/kg 30 mg/kg mg/kg 12
21 mg/kg20 mg/kg30 mg/kg 14 C C-30 mg/kg20 mg/kg 30 mg/kg % 64.5% 95.0% % 67.2% 98.7% % 35.2% 70.0% % 80.6% 96.2% Table Table C- 30 mg/kg % 69.3% 96.5% % 51.4% 27.2% 28.1% 84.8% 79.5% 14 C- 80% 14 C % 35.1% 6.8% 7.4% 42.2% 42.5% 13
22 TK TK 13 TK C max AUC CYP2C CYP3A 12 4 M7 C max 4.5 AUC 24h
23 C max C max (ng/ml) (mg/kg) M1 M2 M3 M4 M5 M6 M a a 30 mg * Table Table Table 2 15 *: 新薬承認情報提供時に置き換えた
24 2.4-5 AUC AUC a (ng h/ml) (mg/kg) M1 M2 M3 M4 M5 M6 M b aauc AUC 24h AUC AUC 24h b 30 mg * Table Table Table 2 16 *: 新薬承認情報提供時に置き換えた
25 2.4.4 M1M in vitro GLP S S P SD mg/kg 1500 mg/kg 1000 mg/kg mg/kg mg/kg mg/kg 30 mg60 kg 0.5 mg/kg SD mg/kg 13 17
26 30 mg/kg 100 mg/kg 100 mg/kg il red mg/kg 2, , mg/kg mg/kg PAS 100 mg/kg PTAPTT 10 mg/kg 100 mg/kg 30 mg/kg 10 mg/kg 30 mg/kg 30 mg 10 AUC * M M6 AUC *: 新薬承認情報提供時に置き換えた
27 mg/kg mg/kg 200 mg/kg 200 mg/kg mg/kg 13 C max 1343 ng/ml, 444 ng/ml 15 in vitro 0.5 µg/ml M1M2M3 M5 30 mg * C max 4 ng/ml M2 20 ng/ml 75 mg/kg 200 mg/kg 75 mg/kg 200 mg/kg 1 ASTALT 4 75 mg/kg mg/kg 75 mg/kg 20 mg/kg 30 mg 10 AUC * *: 新薬承認情報提供時に置き換えた
28 In vitro DA DA µg/ml µg/ml 1 µg/ml24 30 mg 10 AUC * mg AUC G* µg/ml µg/ml µg/ml In vivo 250 mg/kg 125 mg/kg 125 mg/kg 30 mg 10 AUC * mg AUC G* mg/kg 250 mg/kg 125 mg/kg 250 mg/kg 125 mg/kg 30 mg 10 AUC * mg AUC G* *: 新薬承認情報提供時に置き換えた
29 mg/kg mg/kg 100 mg/kg B6C3F mg/kg 100 mg/kg 26 C max : < 50 ng/ml mg/kg mg/kg mg/kg 30 mg 60 kg mg/kg 30 mg/kg 100 mg/kg mg/kg 30 mg 60 kg mg/kg 30 mg/kg 100 mg/kg 200 mg/kg 200 mg/kg 10 mg/kg 100 mg/kg 100 mg/kg mg *-003 AUC *: 新薬承認情報提供時に置き換えた
30 mg/kg 1 40 mg/kg 20 mg/kg 30 mg 60 kg 40 AUC mg/kg 10 mg/kg AUC mg/kg AUC mg/kg 30 mg/kg 100 mg/kg 10 mg/kg 100 mg/kg 30 mg/kg µg/ml 0.5 µg/ml 0.5 µg/ml3 30 mg 10 AUC * mg AUC G* M1M2M3M5 22 *: 新薬承認情報提供時に置き換えた
31 M1M mg/kg 100 mg/kg M5 100 mg/kg M7 100 mg/kg 100 mg/kg 30 mg AUC *-003 M M M M M M6 9.8 M R(+)-R S(-)-S mg/kg 500 mg/kg 2000 mg/kg R S V 2 - SIAD SIAD CPM 16 8 V 2 - V 2 - AUC C max 23 *: 新薬承認情報提供時に置き換えた
32 2.4-6 M1 M2 V 2 - M3M4 M5 AUC C max V 2 - AUC C max M1 M2 M3 M1M2 M3 M14 V 2 - M1 M2 M1M4 M5 M1M2M4 M5 24
33 2.4-6 V 2 - C max AUC 30 mg a 10 mg/kg 30 mg/kg C max M M M M M M M M M M M M M M M M AUC M M M M M M M M M M M M M M M M V 2 - V 2 - Ki / V 2 - Ki 1.00 AUC C max / AUC C max 1.00 a 30 mg *-003 # * V *: 新薬承認情報提供時に置き換えた
34 mg/kg mg/kg 2000 mg/kg mg/kg 100 mg/kg 100 mg/kg 2,3-- PAS 10 mg/kg 30 mg/kg mg/kg 200 µg/kg 75 mg/kg 200 mg/kg 200 mg/kg 75 mg/kg 20 mg/kg in vitro in vivo 1 µg/ml 0.5 µg/ml 100mg/kg B6C3F mg/kg 26 C max : < 50 ng/ml DA 100 mg/kg 26
35 30 mg/kg 100 mg/kg 200 mg/kg 200 mg/kg 40 mg/kg 20 mg/kg 30 mg/kg 100 mg/kg 200 mg/kg 20 mg/kg AD SIAD 30 mg AD SIAD Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988;34: Morel F. Sites of hormone action in the mammalian nephron. Am J Physiol 1981;240:F Ruggles BT, Maruyama, Werness JL, Gapstur SM, Bentley MD, Dousa TP. The vasopressinsensitive adenylate cyclase in collecting tubules and in thick ascending limb of enle s loop of human and canine kidney. J Clin Endocrinol Metab 1985;60: Chabardes D, Gagnan-Brunette M, Imbert-Teboul M, Gontcharevskaia, Montegut M, Clique A, et al. Adenylate cyclase responsiveness to hormones in various portions of the human nephron. J Clin Invest 1980;65: Kleinschmidt-DeMasters BK, orenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 1981;211: Fujisawa G, Ishikawa S, Tsuboi Y, kada K, Saito T. Therapeutic efficacy of non-peptide AD antagonist PC in SIAD rats. Kidney Int 1993;44: Dubb J, Allison, Tatoian D, Blumberg A, Lee K, Stote R. SK&F is antidiuretic in man. Kidney Int 1987;31(abstract):
36 Mah SC, ofbauer KG. Evaluation of the pharmacologic properties of a vasopressin antagonist in Brattleboro rats. J Pharmacol Exp Ther 1988;245: Albrightson-Winslow CR, Caldwell, Brooks DP, uffman WF, Stassen FL, Kinter LB. Cyclooxygenase inhibition unmasks the full antidiuretic agonist activity of the vasopressin antagonist, SK&F , in dogsj Pharmacol Exp Ther 1989; 249: akamura T, Sakamaki T, Kurashina T, oshino J, Sato K, no Z, et al. Effect of vasopressin V 1 (PC-21268) and V 2 (PC-31260) antagonists on renal hemodynamics and excretory function. Life Sci 1994;55:PL Brooks DP, Valente M, Petrone G, Depalma PD, Sbacchi M, Clarke GD. Comparison of the water diuretic activity of kappa receptor agonists and a vasopressin receptor antagonist in dogs. J Pharmacol Exp Ther 1997;280: Kato R, Yamazoe Y. Sex-specific cytochrome P450 as a cause of sex-and species-related difference in drug toxicity. Toxicol Lett 1992; 64/65: ostetler KY. Molecular studies of the induction of cellular phospholipidosis by cationic amphiphilic drugs. Federation Proc 1984;43: Lüllman, Lüllman-Rauch R, Wassermann. Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 1978;27: Aardema MJ, Albertini S, Arni P, enderson LM, Kirsch-Volders M, Mackay JM, et al. Aneuploidy: A report of an ECETC task force. Mutat Res 1998;410:3-79. McClain RM. Phenobarbital mouse liver tumors: Implications of hepatic tumor promotion for cancer risk assessment. In: McClain RM, Slaga TJ, LeBoeuf R, Pitot, editors. Growth factors and tumor promotion. Wiley-Liss, Inc; p Guidelines for carcinogen risk assessment. Federal Register, Wednesday Sep 24, 1986; 51 (185):
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30mg 2 2.6.1 2.6.2 2.6.3 ...i... iii 2.6...1 2.6.1...1 (1)... 1 (2)... 1 (3)... 1 (4)... 1 2.6.2...2 2.6.2.1...2 (1)... 2 (2)... 4 2.6.2.2...6 (1)... 6 (2)... 8 (3) SIAD... 13 (4) V 2 -... 17 (5)... 19
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30mg 2 ...i... iii...1 2.5.1....1 2.5.1.1...1 2.5.1.2...5 2.5.1.3...6 2.5.1.4...15 2.5.1.5 GCP...16 2.5.2...16 2.5.2.1...16 2.5.2.2...17 2.5.2.3...17 2.5.3...18 2.5.3.1...18 2.5.3.2...19 2.5.3.3...23 2.5.3.4...24
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1% 1 mg 1 mg 2 CTD 6 Section 2.6.1 Introduction 2.6.1 H 1 descarboethoxyloratadinesch 34117 7.9 SCH 34117 2.6.1-1 O OC 2 H 5 Cl N N JAN Loratadine (JANINN) ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]
200mg 2005 3 876179 2002 3 3 200mg VFEND for Intravenous Use (1) (2) [4.1 ] (3) [4.2 ] (1) [1] (2) (3) [1] 3
20mg CTD 2.4 2.4 2.4... 5 2.4.1... 5 2.4.2... 7 2.4.3... 10 2.4.4... 13 2.4.5... 18 2.4.6... 20 3 2.4 2.4 2.4.1 JNS002 ( HSPC) N-(Carbonyl-methoxypolyethylene glycol 2000)-1,2- distearoyl-sn-glycero-3-phosphoethanolamine
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(1) (2) (1) (2) (1) Seg (2) Seg (3) Seg (4) Seg (1) (2) (3) ( ) (1) (PCA)...12
(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
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2. 2 1. 1) 2) 2 Crj:CD(SD)IGS SPF 0 240 1200 6000 ppm 2 F0 10 F0 10 F1 21 F1 3 10 F1 3 10 F2 21 0 240 1200 6000 ppm 1 F0 0 15.88 79.57 401.8 mg/kg/day F0 0 20.80 104.19 510.7 mg/kg/day F1 0 17.84 89.89
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 () - 1 - - 2 - - 3 - - 4 - - 5 - 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57
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