Validation of a biophysical drug absorption model by the PATQSAR system.
Absorption rate constants (in situ rat gut technique) and in vitro antibacterial activities of twenty fluoroquinolones have been evaluated. A biophysical model that relates the absorption of the compounds with their lipophilicity was fitted. The model considers the absorption process from the intestinal lumen as the sum of two resistances in series: aqueous diffusional barrier and lipoidal membrane. Even if partitioning into the membrane and membrane diffusion are both enhanced for lipophilic compounds, the absorption rate constant is limited by the aqueous diffusion. To estimate the influence of structural modifications on each property and to establish the role of lipophilicity in controlling in situ absorption and in vitro antibacterial activity, the PATQSAR search system is used to construct structure-property relationships. The structural models, which explain 99% of the total variance of each physicochemical property and 96% of each in vitro biological activity, provide an explicit and precise interpretation of lipophilicity, absorption, and antimicrobial activity. The results confirm the important role of lipophilicity in controlling absorption, as pointed out by the biophysical model for the piperazinyl series, and suggest the introduction of electronic factors in order to extend the model to heterologues. They also justify the mechanism by which quinolones are assumed to induce antibacterial activity.
Bermejo
M
M
Department of Pharmaceutics, Faculty of Pharmacy, University of Valencia, Spain.
Merino
V
V
Garrigues
T M
TM
Pla Delfina
J M
JM
Mulet
A
A
Vizet
P
P
Trouiller
G
G
Mercier
C
C
D000465:Algorithms; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D055592:Biophysical Phenomena; D001703:Biophysics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D024841:Fluoroquinolones; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology*; D008055:Lipids / Q000737:chemistry; D008297:Male; D008954:Models, Biological; D008961:Models, Structural; D011153:Population; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D008055:Lipids