Biophysical models as an approach to study passive absorption in drug development: 6-fluoroquinolones.
A preliminary study attempting to assess and explain the intestinal absorption of a series of antibacterial 7-piperazinyl-6-fluoroquinolones is presented. The synthesis, n-octanol partition coefficients, intrinsic rat gut in situ absorption rate constants, and in vitro antibacterial activity data found for these homologous compounds are described. A fluorimetric, reverse-phase HPLC method was performed for the quantification of the quinolones in absorption and partition samples. Equations based on two classic biophysical absorption models are given for predicting the intrinsic absorption features of the series according to the partition data or merely single structural parameters. In situ absorption rate constants were found to increase by a factor of 9.7-13.5 for moderately lipophilic derivatives relative to the simplest compound, while antibacterial activity decreased only by a factor of 4. In vivo absorption tests with two representative members of the series were carried out and the results showed a good accordance with those found in situ. This makes these compounds or related ones with similar partition features excellent candidates for further pharmacokinetic and pharmacological testing. The study can serve as an example of how to prevent potential absorption problems associated with the development of new drugs.
Merino
V
V
Department of Pharmaceutics, Faculty of Pharmacy, University of Valencia, Spain.
Freixas
J
J
del Val Bermejo
M
M
Garrigues
T M
TM
Moreno
J
J
Plá-Delfina
J M
JM
D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001702:Biopharmaceutics; D055592:Biophysical Phenomena; D001703:Biophysics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D024841:Fluoroquinolones; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008055:Lipids / Q000737:chemistry; D008297:Male; D008954:Models, Biological; D008970:Molecular Weight; D051381:Rats; D017208:Rats, Wistar
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D008055:Lipids