The advantages of the Ussing chamber in drug absorption studies.
By adding high concentrations of test drugs to an Ussing chamber with rat jejunum, we established a system that yields very high correlations between the rat absorption percentage and the membrane permeability, and that can accurately predict the absorption percentage for rats. An advantage of this technique is that, unlike the results obtained using Caco-2, the slope of the absorption/membrane-permeability curve is gentle, which facilitates a more exact prediction of the absorption percentage. In addition, the results obtained with this technique demonstrated that it could be used to evaluate the absorption percentage of drugs with an affinity for P-glycoprotein (P-gp), which cannot be assessed using Caco-2. This method also allows for cassette screening, which would facilitate evaluation of the contribution of P-gp to absorption in the small intestine. Cassette screening showed that absorption of fexofenadine was unaffected by combination with the P-gp substrate ketoconazole. Consistent with this finding, in vivo studies showed that ketoconazole did not affect the Fa Fg for fexofenadine, a pharmacokinetic parameter that reflects absorption and bioavailability in the small intestine. This confirms the usefulness of the Ussing chamber for cassette screening and also suggests that intestinal P-gp has a minimal contribution to drug absorption.
Gotoh
Yasumasa
Y
Division of Basic Discovery Research, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. yasumasa_goto@pharm.kissei.co.jp
Kamada
Noboru
N
Momose
Denichi
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000042:Absorption; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004341:Drug Evaluation / Q000295:instrumentation* / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation* / Q000379:methods; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D013058:Mass Spectrometry; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016593:Terfenadine; C093230:fexofenadine; D007654:Ketoconazole