A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

被引：19

作者：

Cui, Yunhai ^{[1
]}

Desevaux, Cyril ^{[2
]}

Truebenbach, Ines ^{[1
]}

Sieger, Peter ^{[1
]}

Klinder, Klaus ^{[1
]}

Long, Alan ^{[3
,4
]}

Sauer, Achim ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Drug Discovery Sci, D-88397 Biberach, Germany

[2] Boehringer Ingelheim Anim Hlth, Exploratory Toxicol & Pharmacokinet, Athens, GA 30601 USA

[3] Boehringer Ingelheim Anim Hlth, Chem & Lead Optimizat, Athens, GA 30601 USA

[4] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Med Chem, D-88397 Biberach, Germany

来源：

PHARMACEUTICS | 2021年 / 13卷 / 08期

关键词：

permeability; physiological barrier; efflux; drug transporter; Lipinski's Rule of 5; oral bioavailability; depsipeptides; IN-VITRO; ORAL ABSORPTION; CYCLOSPORINE; TRANSPORT; SOLUBILITY; PROPERTY; BINDING;

D O I：

10.3390/pharmaceutics13081146

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances across physiological barriers. With the increasing number of investigative drugs coming from chemical space beyond Lipinski's Rule of 5, it becomes more and more challenging to provide meaningful data with the standard permeability assay. This is exemplified here by the difficulties we encountered with the cyclic depsipeptides emodepside and its close analogs with molecular weight beyond 1000 daltons and cLogP beyond 5. The aim of this study is to identify potential reasons for these challenges and modify the permeability assays accordingly. With the modified assay, intrinsic permeability and in vitro efflux of depsipeptides could be measured reliably. The improved correlation to in vivo bioavailability and tissue distribution data indicated the usefulness of the modified permeability assay for the in vitro screening of compounds beyond the Rule of 5.

引用

页数：14

共 28 条

[1] Binding of a fluorescent lipid amphiphile to albumin and its transfer to lipid bilayer membranes [J].

Abreu, MSC ;

Estronca, LMBB ;

Moreno, MJ ;

Vaz, WLC .

BIOPHYSICAL JOURNAL, 2003, 84 (01) :386-399

[2] Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques [J].

Beyer, Susanne ;

Xie, Li ;

Schmidt, Mike ;

de Bruin, Natasja ;

Ashtikar, Mukul ;

Rueschenbaum, Sabrina ;

Lange, Christian M. ;

Vogel, Vitali ;

Maentele, Werner ;

Parnham, Michael J. ;

Wacker, Matthias G. .

JOURNAL OF CONTROLLED RELEASE, 2016, 235 :352-364

[3] TISSUE DISTRIBUTION AND TOXICITY OF CYCLOSPORIN A IN THE MOUSE [J].

BOLAND, J ;

ATKINSON, K ;

BRITTON, K ;

DARVENIZA, P ;

JOHNSON, S ;

BIGGS, J .

PATHOLOGY, 1984, 16 (02) :117-123

[4] Quantification of Transporter and Receptor Proteins in Dog Brain Capillaries and Choroid Plexus: Relevance for the Distribution in Brain and CSF of Selected BCRP and P-gp Substrates [J].

Braun, Clemens ;

Sakamoto, Atsushi ;

Fuchs, Holger ;

Ishiguro, Naoki ;

Suzuki, Shinobu ;

Cui, Yunhai ;

Klinder, Klaus ;

Watanabe, Michitoshi ;

Terasaki, Tetsuya ;

Sauer, Achim .

MOLECULAR PHARMACEUTICS, 2017, 14 (10) :3436-3447

[5] Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood-Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery [J].

Cui, Yunhai ;

Lotz, Ralf ;

Rapp, Hermann ;

Klinder, Klaus ;

Himstedt, Anneke ;

Sauer, Achim .

PHARMACEUTICS, 2019, 11 (11)

[6] Method for measuring the logarithm of the octanol-water partition coefficient by using short octadecyl-poly(vinyl alcohol) high-performance liquid chromatography columns [J].

Donovan, SF ;

Pescatore, MC .

JOURNAL OF CHROMATOGRAPHY A, 2002, 952 (1-2) :47-61

[7] Brain penetration of emodepside is increased in P-glycoprotein-deficient mice and leads to neurotoxicosis [J].

Elmshaeuser, S. ;

Straehle, L. C. ;

Kranz, J. ;

Krebber, R. ;

Geyer, J. .

JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS, 2015, 38 (01) :74-79

[8] CYCLOSPORINE - A REVIEW OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES, AND THERAPEUTIC USE IN IMMUNOREGULATORY DISORDERS [J].

FAULDS, D ;

GOA, KL ;

BENFIELD, P .

DRUGS, 1993, 45 (06) :953-1040

[9] In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system [J].

Feng, Bo ;

Mills, Jessica B. ;

Davidson, Ralph E. ;

Mireles, Rouchelle J. ;

Janiszewski, John S. ;

Troutman, Matthew D. ;

de Morais, Sonia M. .

DRUG METABOLISM AND DISPOSITION, 2008, 36 (02) :268-275

[10] Safety, tolerability and pharmacokinetics of emodepside, a potential novel treatment for onchocerciasis (river blindness), in healthy male subjects [J].

Gillon, Jean-Yves ;

Dennison, Jeremy ;

van den Berg, Frans ;

Delhomme, Sophie ;

Dequatre Cheeseman, Karen ;

Pena Rossi, Claudia ;

Strub Wourgaft, Nathalie ;

Specht, Sabine ;

Pedrique, Belen ;

Monnot, Frederic ;

Skrabs, Susanne ;

Rodriguez, Maria-Luisa ;

Stass, Heino .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2021, 87 (10) :3949-3960

← 1 2 3 →