PAMPA—a drug absorption in vitro model: 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones

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• 作者：Bermejo ; Marival ; Avdeef ; Alex ; Ruiz ; Ana ; Nalda ; Ricardo ; Ruell ; Jeffrey A. ; Tsinman ; Oksana ; et. al.
• 关键词：PAMPA ; Caco-2 ; Fluoroquinolones ; Permeability ; Unstirred water layer ; Oral absorption
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2004
• 期刊代码：15_09280987
• 类别：pha
• 出版时间：March, 2004
• 卷：21
• 期：4
• 页码：429-441
• 文件大小：288 K

摘要

Parallel artificial membrane permeability assay (PAMPA) was used to measure the effective permeability, P_e, as a function of pH from 4 to 10, of 17 fluoroquinolones, including three congeneric series with systematically varied alkyl chain length at the 4′N-position of the piperazine residue. The permeability values spanned over three orders of magnitude. The intrinsic permeability, P_o, and the membrane permeability, P_m, were determined from the pH dependence of the effective permeability. The pK_a values were determined potentiometrically. The PAMPA method employed stirring, adjusted such that the unstirred water layer (UWL) thickness matched the 30–100μm range estimated to be in the human small intestine. The intrinsic permeability coefficients (10⁻⁶cm/s), representing the permeability of the uncharged form of the drug, are for 4′N-R-norfloxacin: 0.7 (R=H), 49 (Me), 132 (n-Pr), 365 (n-Bu); 4′N-R-ciprofloxacin: 2.7 (H), 37 (Me), 137 (n-Pr), 302 (n-Bu); 4′N-R-3′-methylciprofloxacin: 3.8 (H), 20 (Me), 51 (Et), 160 (n-Pr), 418 (n-Bu). Increasing the alkyl chain length in the congeneric series resulted in increased permeability, averaging about 0.34log units per methylene group, except that of the first (H-to-Me), which was about 1.2log units. These results were compared to Caco-2 and rat in situ permeability measurements. The in situ closed loop technique used for obtaining permeability values in rat showed a water layer thickness effect quite consistent with in vivo expectations. The rat–PAMPA correlation (r²