Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates

Membrane and Dye Efflux Assays to Detect and Characterize the Interaction of Drugs with ABC Transporters

Author(s): Eniko Ioja, Zoltan Nagy, Viktoria Juhasz, Judit Janossy, Krisztina Heredi-Szabo and Peter Krajcsi

Pp: 102-116 (15)

DOI: 10.2174/978160805120511101010102

* (Excluding Mailing and Handling)

Abstract

The aim of this chapter is to describe the main in vitro assays used to predict the interaction of drugs with ABC efflux transporters, to highlight their characteristics and to discuss their advantages and disadvantages. In recent years, the number of synthesized compounds has increased dramatically as a result of advances in combinatorial chemistry; consequently, early prediction of the interactions of drug-like compounds with efflux transporters has garnered considerable attention. Moreover, transporter-related drug-drug interactions, particularly in specific groups (children and the elderly), are of great concern. The withdrawal of marketed drugs and the failure of drugs in the late clinical phase of drug research is often due to drug-drug interactions. Furthermore, regulatory authorities require information on the potential for interactions to cause adverse effects: a question that might be answered by in vitro assays even in the early stages of discovery. In vivo studies and cellbased assays such as CaCo-2 monolayers have been elaborated, as well as quite expensive screening modes that are primarily used for screening large numbers of compounds. By scaling the discussed in vitro assays up to medium- or high-throughput screening modes, these assays can be efficiently used for the prediction of active transport and transporter-mediated drug-drug interactions, and may be the most cost-effective approach to transporter screening in drug discovery.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51322660 and j.to_ip >=51322660 )) and ((j.from_date <= 1740473403 and j.to_date >= 1740473403 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2822) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51322660 and j.to_ip >=51322660 )) and ((j.from_date <= 1740473403 and j.to_date >= 1740473403 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2822) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51322660 and j.to_ip >=51322660 )) and ((j.from_date <= 1740473403 and j.to_date >= 1740473403 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2822)
      790μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 983 and `b`.`banner_from_date` <= 1740473403 and `b`.`banner_to_date` >= 1740473403 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.04msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 983
      • 3: 1740473403
      • 4: 1740473403
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='9c89818563127fb741c778672cbac2a2'
      210μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Keywords
    1Keywords.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        sTUCWK1P75g636q6WXM1YVM3PHdNunL7OkiylACR
        uc_cart_id
        9c89818563127fb741c778672cbac2a2
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2822" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/2822
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Iit1Y1JtN3F6dVVybFJuZlMvZzZSN0E9PSIsInZhbHVlIjoiaXgySlpGang4azZTWTl6YURPdHQ3Qy9CQXdOaC9WSFJxY2U3dnZzMmRsVT0iLCJtYWMiOiIwODcwMTdmZGUxZmU3MTFmMzc0NWZiM2VlYTlkZDc5YTljNWEwNDEzN2FiNzFmZmIzNmMwZmE5Nzg4YWVmNWY5IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Iit1Y1JtN3F6dVVybFJuZlMvZzZSN0E9PSIsInZhbHVlIjoiaXgySlpGang4azZTWTl6YURPdHQ3Qy9CQXdOaC9WSFJxY2U3dnZzMmRsVT0iLCJtYWMiOiIwODcwMTdmZGUxZmU3" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 08:50:03 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ikt1S0lUam9aQjNQdU5xeW1wMDJ5QXc9PSIsInZhbHVlIjoiWURrdzRORmZyN3FUdEVCZ0l0QkkwNzFDME5XZ0o4SmRtU0JwbFRSRHVKVUF0SXowTTdqb2x5SXptSkJKQVdiamVPMm53dnpDSlVkU2lmdnh0d24vRlpPMkFEOXZkOEVySm91TmhzTUQwVWR5YWNCSlNocW4xMUt0NThzTkRiN2MiLCJtYWMiOiJhNTgyNmIyYzI4ODQ1ZDBiMGIxNDE3YTM1MTFiYzQ1ZDIzNDRmZDM1ODFhY2M4ODI2YjZjMjhmNTFjNDMzNjFlIiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 20:50:03 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Ikt1S0lUam9aQjNQdU5xeW1wMDJ5QXc9PSIsInZhbHVlIjoiWURrdzRORmZyN3FUdEVCZ0l0QkkwNzFDME5XZ0o4SmRtU0JwbFRSRHVKVUF0SXowTTdqb2x5SXptSkJKQVdiamVPMm53d" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ik9SaFE5R3hOUEVVWmErenZmVmk0Wmc9PSIsInZhbHVlIjoiakFyZEZxK3BnMWxJc0VSd3ZITEZwdi95dGhZTE9IU1k4ZlNnK1licVFISG5ETDg5TmZNaU5TVUZUUGU2eXNxZUcxQ0ZuWERUSGJuTGg3Q1pydzNvMnNJYkpISmw5UU5xMzlVWmVuai9vTDExd1g0SHN0YWxpS1NxNTU1am5VSmkiLCJtYWMiOiJlMGMxNjI0NWQ5ZjU3NDMzNWQ5M2VlN2RlZTQwMTdmNGY1MDZhODZjNTg0MDFmMGI4ZTJmNmM1NDUzYzQ1NTI0IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Ik9SaFE5R3hOUEVVWmErenZmVmk0Wmc9PSIsInZhbHVlIjoiakFyZEZxK3BnMWxJc0VSd3ZITEZwdi95dGhZTE9IU1k4ZlNnK1licVFISG5ETDg5TmZNaU5TVUZ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ikt1S0lUam9aQjNQdU5xeW1wMDJ5QXc9PSIsInZhbHVlIjoiWURrdzRORmZyN3FUdEVCZ0l0QkkwNzFDME5XZ0o4SmRtU0JwbFRSRHVKVUF0SXowTTdqb2x5SXptSkJKQVdiamVPMm53dnpDSlVkU2lmdnh0d24vRlpPMkFEOXZkOEVySm91TmhzTUQwVWR5YWNCSlNocW4xMUt0NThzTkRiN2MiLCJtYWMiOiJhNTgyNmIyYzI4ODQ1ZDBiMGIxNDE3YTM1MTFiYzQ1ZDIzNDRmZDM1ODFhY2M4ODI2YjZjMjhmNTFjNDMzNjFlIiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 20:50:03 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Ikt1S0lUam9aQjNQdU5xeW1wMDJ5QXc9PSIsInZhbHVlIjoiWURrdzRORmZyN3FUdEVCZ0l0QkkwNzFDME5XZ0o4SmRtU0JwbFRSRHVKVUF0SXowTTdqb2x5SXptSkJKQVdiamVPMm53d" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ik9SaFE5R3hOUEVVWmErenZmVmk0Wmc9PSIsInZhbHVlIjoiakFyZEZxK3BnMWxJc0VSd3ZITEZwdi95dGhZTE9IU1k4ZlNnK1licVFISG5ETDg5TmZNaU5TVUZUUGU2eXNxZUcxQ0ZuWERUSGJuTGg3Q1pydzNvMnNJYkpISmw5UU5xMzlVWmVuai9vTDExd1g0SHN0YWxpS1NxNTU1am5VSmkiLCJtYWMiOiJlMGMxNjI0NWQ5ZjU3NDMzNWQ5M2VlN2RlZTQwMTdmNGY1MDZhODZjNTg0MDFmMGI4ZTJmNmM1NDUzYzQ1NTI0IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Ik9SaFE5R3hOUEVVWmErenZmVmk0Wmc9PSIsInZhbHVlIjoiakFyZEZxK3BnMWxJc0VSd3ZITEZwdi95dGhZTE9IU1k4ZlNnK1licVFISG5ETDg5TmZNaU5TVUZ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "sTUCWK1P75g636q6WXM1YVM3PHdNunL7OkiylACR" "uc_cart_id" => "9c89818563127fb741c778672cbac2a2" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2822" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 08:50:03GET/chapter/2822112193