A novel approach to determining physicochemical and absorption properties of 6-fluoroquinolone derivatives: experimental assessment

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 53; no. 3; pp. 317 - 325
• Main Authors: Cabrera Pérez, Miguel Angel, González Dı́az, Humberto, Fernández Teruel, Carlos, Plá-Delfina, José M a, Bermejo Sanz, Marival
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.05.2002; Elsevier Science
• Subjects: 6-Fluoroquinolone; Absorption; Animals; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacokinetics; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Fluoroquinolones - chemistry; Fluoroquinolones - pharmacokinetics; Intestinal Absorption; Male; Medical sciences; Models, Biological; Pharmacology. Drug treatments; Physicochemical property; Rats; Rats, Wistar; Sarafloxacin; Sparfloxacin; Structure-Activity Relationship; Structure–property relationship; ToSS MoDe approach; Absorption; Physicochemical property; ToSS MoDe approach; Sparfloxacin; Sarafloxacin; 6-Fluoroquinolone; Structure–property relationship; Fluoroquinolone derivatives; Analog; Prediction; Oral administration; Property structure relationship; Antibacterial agent; Mathematical model; Physicochemical properties; Quinolone derivatives
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/S0939-6411(02)00013-9

The ToSS MoDe approach is used to estimate the n-octanol/buffer partition coefficient, the apparent intestinal absorption rate constant and intestinal permeability from a 6-fluoroquinolone data set. Improved in silico methods for predicting a drug's ability to be transported across biological membranes and other biopharmaceutical properties is highly desirable to optimize new drug development. The physicochemical property (Log P) of 26 6-fluoroquinolone derivatives and the absorption properties (Log K a and Log P eff) of 21 derivatives were well described by the present approach. The models obtained confirm the important role of lipophilicity in the absorption process and its relation with the piperazinyl ring spectral moment and general local spectral moment. The normalized group contributions to each property, at the R 4 and R 5 positions of a 6-fluoroquinolone framework, were calculated. Principal factor analysis between these contributions and the Hammett and Hansch constant, molar refractivity and sterimol parameters was also carried out. Three principal factors explained 78% of the total variance and the correlation coefficients were higher than 0.98. The isocontribution zone analysis for the Log P and Log K a of Sarafloxacin and Sparfloxacin, used as external corroboration compounds, was carried out. The absorption rate constants (in situ rat gut technique) for these drugs were also evaluated, and the results were compared with the values predicted by theoretical models for evaluating predictive performance. The present approach proved to be a good method for studying the oral absorption of drug candidates in drug development studies.