title: Prediction of absorbability of poorly water-soluble drugs based on permeability obtained through modified in vitro chamber method.
abstract: Permeability is an underlying parameter to control drug absorption. For highly water-soluble drugs, the high correlation between their permeability and fraction absorbed in humans is reported. In the present study, to predict the absorbability of poorly water-soluble drugs in humans, a new experimental method of the permeation study was proposed and subjected to examination. Firstly, using the in vitro chamber method modified to contain 5% (final concentration) dimethyl sulufoxide (DMSO) in both compartments of the chamber (DMSO-MS), the effect of DMSO on membrane integrity was evaluated. Secondly, the correlation between the apparent permeability coefficients (Papp) obtained through DMSO-M or DMSO-MS and fractions absorbed in humans were investigated using 7 poorly water-soluble drugs. Membrane integrity of the rat intestinal tissues was maintained after using DMSO-MS, as with that after using the conventional in vitro chamber method. Papp of two paracellular markers obtained through DMSO-MS was not different from that obtained through the conventional chamber method. In the permeation study of the P-glycoprotein substrate, Papp from both mucosal to serosal and serosal to mucosal sides obtained through DMSO-MS was not significantly different from that obtained through the conventional chamber method. The correlation between Papp obtained through DMSO-MS and Fa which was expressed by the equation of Fa=1-exp (-Pappx1.38x10(5)) (r2=0.980), was more favorable than the correlation between Papp obtained through DMSO-M and Fa which was expressed by the equation of Fa=1-exp (-Pappx2.12x10(5)) (r2=0.875). These results showed that DMSO-MS was a useful method for predicting the absorbability of poorly water-soluble drugs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan. watanqsf@daiichipharm.co.jp
authors.forename: Etsushi
authors.initials: E
authors.lastname: Watanabe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D000042:Absorption; D000465:Algorithms; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D000983:Antipyrine / Q000737:chemistry / Q000378:metabolism; D003911:Dextrans; D004121:Dimethyl Sulfoxide; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D005456:Fluorescent Dyes; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D012460:Sulfasalazine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003911:Dextrans; D005456:Fluorescent Dyes; D005765:Gastrointestinal Agents; D004364:Pharmaceutical Preparations; C015219:fluorescein isothiocyanate dextran; D020112:Rhodamine 123; D012460:Sulfasalazine; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase; D016650:Fluorescein-5-isothiocyanate; D000983:Antipyrine; D004121:Dimethyl Sulfoxide