Prediction of the permeability of drugs through study on quantitative structure-permeability relationship.
This study is to research the quantitative structure-permeability relationship of 20 drugs having similar structure. Permeability was determined by using the Caco-2 cell in vitro model. The apparent permeability coefficient (Papp) of each drug both of apical to basolateral side and basolateral to apical side was measured at the concentration corresponding to 0.1 times the highest dose strength of 250 mL dissolved buffer. In order to test the permeability system suitability, we measured the Papp of 19 model drugs out of 20 which presented in 'Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms based on the Biopharmaceutics Classification System' of FDA guidance. Also, we demonstrated the functional expression of efflux systems (e.g., p-gp) by bi-directional transport studies with rhodamine 123. Also, as a result of the study on quantitative structure-permeability relationship by using the partial least square method, it was possible to predict the permeability of drugs from their 3D structure. The quantitative structure-permeability relationship provided a cross-validated q2=0.789, a normal r2=0.998. Considering all of above results, analysis on this quantitative structure-permeability relationship appears to be a very useful tool to predict the permeability.
Jung
Seo Jeong
SJ
Division of Biopharmaceutics, Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, #231 Jinheungno, Eunpyung-Gu, Seoul, Republic of Korea.
Choi
Sun Ok
SO
Um
So Young
SY
Kim
Joo Il
JI
Choo
Hae Young Park
HY
Choi
Su Young
SY
Chung
Soo Youn
SY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003198:Computer Simulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D013223:Statistics as Topic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal