MRP. parallel artificial membrane permeation assay (PAMPA) Caco-,

Size: px

Start display at page:

Download "MRP. parallel artificial membrane permeation assay (PAMPA) Caco-,"

Derek Neal
5 years ago
Views:

1 parallel artificial membrane permeation assay (PAMPA) Caco-, Caco-, Prediction of Human Oral Absorption of Chemicals in the Environment Miki AKAMATSU, Masaaki FUJIKAWA, Kazuya NAKAO, Ryo SHIMIZU, +, P- P-gp MRP +

2 P-gp MRP ABC, ATP Caco-, Caco-, - PAMPA QSAR parallel artificial membrane permeation assay (PAMPA) +. in vitro 30 PAMPA DMSO ph 1.- DMSO ph 1.- P app-pampa Sugano / Wohnsland 0 PAMPA Avdeef PAMPA 1, 2 + PAMPA PAMPA PAMPA Quantitative Structure- Activity Relationship : QSAR QSAR QSAR QSAR PAMPA classical QSAR Hansch-Fujita 3 ph 1.- PAMPA P app-pampa +* PAMPA PAMPA Caco-, Caco-, PAMPA +- / log P oct pk a ph pk a ph 1.- ph * [log P oct pk a ph ] ph log P oct,pk a van der Waals SA HA, SA HD

3 van der Waals Sybyl ++ PAMPA QSAR PAMPA QSAR + log P app-pampa *..- log P oct *.,/ pk a ph +.*1 SA HA +.** SA HD..32 (+) n /1 s *.-- r, *.10 q, *.1, n, s, r, q, leave-one-out + QSAR QSAR Desipramine, Imipramine Testosterone + + PAMPA + +*, P app-pampa +,,-A log P app-pampa + log P app-pampa../../../ I../ II, QSAR, - I( log P app-pampa../) log P app-pampa *.., log P oct *.,2 pk a ph +.,* SA HA +.++ SA HD..13 (,) n 1+ s *.-/ r, *.10 q, *.1, II ( log P app-pampa../) log P app-pampa *.0, log P oct *.-3 pk a ph -.+, (-) n -+ s *.., r, *.0- q, *.// I, + II log P app-pampa, - log P app-pampa bilinear [log P oct *.01 pk a ph ] log P app bilinear pk a ph *.01, log P oct pk a ph Bilinear log P oct bilinear Kubinyi +- I II bilinear. log P app-pampa *./- log P app +..- log (b+* log P app +) *.2, SA HA +.+1 SA HD..33 (.) n +*, s *.-3 r, *.1+ q, *.01 log P app (optimum),.*3 log b,.-,, QSAR PAMPA A + B.

4 log P app,.*3 log P app *./- log P app-pampa log P app,.*3 log P app-pampa log P app *.3* ( *./- +..-) +, - log P oct,pk a, SA HA SA HD bilinear,-b. log P app-pampa PAMPA +, log P oct PAMPA, R P M + PAMPA I II P app-pampa I PAMPA II PAMPA PAMPA Caco-, Caco-, apical basolateral basolateral apical +. Caco-, Absorption Systems LP (USA) Caco-, - +*, +,, +/ apical basolateral basolateral apical A (B) apical basolateral (C) basolateral apical - Caco-, apical basolateral Caco-, +0 Caco-, PAMPA apical basolateral Caco-, - A A -/ log P app-caco-, log P app-pampa /. - PAMPA Caco-,

5 log P app-caco-, +.*- log P app-pampa *..3 (/) n -/, s *.-/, r, *.10, q, *.1- / + log P app-pampa log P app-caco-, + : + B indole---acetamide, indole- --carboxilic acid, indole---acetic acid, indole--- propionic acid, salicylic acid, N Caco-, A C Ac-Trp-Val-NH,,Ac-9-Trp-Val- NH,, cyclo(trp-trp) P-gp - A B C / Caco-, PAMPA Caco-, Caco-, - in silico. Chlorpyrifos Di(,-ethylhexyl)phthalate Chlorpyrifos (log P oct..2, ; pk a ph* ; SA HA *..11 ; SA HD *) 3/ ( 1,, 3- ), Di(,-ethylhexyl) phthalate (log P oct 1../ ; pk a ph * ; SA HA *./*/ ; SA HD *) * ( +- ). in silico Bilinear QSAR Caco-, + : + Bioconcentration Factor, BCF : / ( ) BCF BCF BCF log P oct 0 log BCF log P oct PAMPA log P M BCF log P oct +1 PAMPA PAMPA QSAR log P oct QSAR

6 +) K. Palm, P. Artursson & K. Luthman : Computer- Assisted Lead Finding and Optimization : Current Tools for Medicinal Chemistry, ed. by H. van de Waterbeemd et al., Wiley-VCH, Weinheim, Germany, +331, p.,13.,) K. Ueda, M. M. Cornwell, M. M. Gottesman, I. Pastan, I. B. Roninson, V. Ling & J. R. Riordan : Biochem. Biophys. Res. Commun., +.+, 3/0 (+320). -) P. Artursson & J. Karlsson : Biochem. Biophys. Res. Commun., +1/, 22* (+33+)..) M. Kansy, F. Senner & K. Gubernator : J. Med. Chem.,.+, +**1 (+332). /) K. Sugano, N. Takata, M. Machida, K. Saitoh & K. Terada : Int. J. Pharm.,,.+,,.+ (,**,). 0) F. Wohnsland & B. Faller : J. Med. Chem.,.., 3,- (,**+). 1) A. Avdeef : Absorption and Drug Development, ed. by A. Avdeef, John Wiley & Sons, Inc., Hoboken, NJ, USA,,**-. 2) A. Avdeef & O. Tsinman : Eur. J. Pharm. Sci.,,2,.- (,**0). 3) C. Hansch & T. Fujita : J. Am. Chem. Soc., 20, +0+0 (+30.). +*) M. Fujikawa, R. Ano, K. Nakao, R. Shimizu & M. Akamatsu : Bioorg. Med. Chem., +-,.1,+ (,**/). ++) SYBYL Molecular Modeling Software, Tripos Associates, Inc., St Louis, MO, USA. +,) M. Fujikawa, K. Nakao, R. Shimizu & M. Akamatsu : Bioorg. Med. Chem., +/, -1/0 (,**1). +-) H. Kubinyi : J. Med. Chem.,,*, 0,/ (+311). +.) R. Ano, Y. Kimura, M. Urakami, M. Shima, R. Matsuno, T. Ueno & M. Akamatsu : Bioorg. Med. Chem., +,,,.3 (,**.). +/) R. Ano, Y. Kimura, M. Shima, R. Matsuno, T. Ueno & M. Akamatsu : Bioorg. Med. Chem., +,,,/1 (,**.). +0) M. Yazdanian, S. L. Glynn, J. L. Wright & A. Hawa : Pharm. Res., +/, +.3* (+332). +1) -/ p. -- (,**1) Kunihiro Shiomi +33, +332 DC, PD,***,**1 Ryo Shimizu ,**1,**-,**. QSAR B Mikako Shirouzu +33* +33/,**+,**1 X Hiroshi Takeshima / Hirofumi Tachibana Hirotaka Chida,**,,**.,**1

Quantitative Structure-Activity Relationships : QSAR

Quantitative Structure-Activity Relationships : QSAR !" () * 56 &% ' 78 +, -. () * // // 0% 12 // // 34 12 #$ % ADME/Tox Absorption Distribution Metabolism Excretion Toxicity ADME/Tox Absorption Distribution