title: An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs.
abstract: We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble drugs and ester prodrug pivampicillin. This evaluation system includes a drug-dissolving vessel (DDV, assumed stomach), a pH adjustment vessel (PAV, assumed intestine) and a side-by-side diffusion chamber that is mounted by a Caco-2 monolayer, which is grown on a polycarbonate filter, or by a rat intestine between the donor and receiver compartments. Our proposed system can accommodate large amounts of solid drugs, simulating a drastic pH change process in GI tract, that is, an orally administered solid drug is dissolved in the stomach (pH 1-2) and transferred to the intestine (pH 6), and that dissolution process can also be monitored. The optimal flow rates for our system are 0.35-1.10 ml/min. Using this system, cumulative permeations of eight relatively water-soluble drugs were compared, and these cumulative permeations indicated the ability of drug absorption in humans. Drugs that permeated across a Caco-2 monolayer at cumulative permeation of more than 0.03% or over 0.04% in rat intestine can be almost completely absorbed in humans. If the cumulative permeation across a Caco-2 monolayer is lower than 0.03% or below 0.04% in the rat intestine, there was a good linear correlation between cumulative permeation across a Caco-2 monolayer and oral absorption in humans, or between cumulative permeation across a rat intestine and oral absorption in humans. In the case of relatively water-soluble drugs, a good linear correlation was obtained between cumulative permeation across a Caco-2 monolayer and cumulative permeation across a rat intestine. This result indicates that it is possible to predict the oral absorption of a relatively water-soluble drug in humans based on the cumulative permeation of the drug across a Caco-2 monolayer and/or a rat intestine. The time course of permeation of the ester prodrug pivampicillin, which is metabolized in a Caco-2 monolayer or in a rat intestine, was also evaluated. It stated clearly that it is also possible to predict the oral absorption of pivampicillin in humans based on the cumulative permeation across a Caco-2 monolayer or rat intestine. Our newly developed system enables more kinds of oral preparations and also pH-dependent soluble drugs to be evaluated.
authors.affiliation: Department of Pharmacy, School of Medicine, Hokkaido University Hospital, Kita-14-jo, Nishi-5-chome, Kita-ku, Sapporo 060-8648, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sugawara
authors.forename: Michiya
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takekuma
authors.forename: Katsumi
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells / Q000378:metabolism; D004952:Esters; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011237:Predictive Value of Tests; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility / Q000187:drug effects; D014867:Water / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004952:Esters; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D014867:Water