title: Increased understanding of intestinal drug permeability determined by the LOC-I-GUT approach using multislice computed tomography.
abstract: This study further evaluated the in vivo single-pass perfusion technique (LOC-I-GUT) in three different ways. First, the intestinal radius of the human small intestinal segment was measured on plain X-ray films; second, evaluation was performed by applying multislice computed tomography investigations; and third, furosemide was used as model drug in a transport study. In total 17 (6 + 4 +7) intubation/perfusion studies were performed in healthy volunteers. Mixobar was used as a positive radiographic contrast agent in the first six volunteers when plain film examination was made, followed by four studies using multislice computed tomography. Mantel area calculations of the perfused segment after X-ray investigations using barium as contrast were determined to be 101.0 +/- 2.9 cm2. Maximal dilatation of the closed segment with room air as contrast and using MSCT revealed a mantel area of 121.30 +/- 7.0 cm2 (P < 0.01). Thus, the mantle area increased a further 20% when the bowel was fully distended, reflecting different physiologic distention patterns for air and fluid. A jejunal single-pass perfusion study was performed in a further seven volunteers. In each experiment furosemide was perfused during 200 min, and in the treatment period (100-200 min), fexofenadine was added to the perfusion solution. The mean (+/-SD) P (eff) for furosemide was 0.17 +/- 0.07 and 0.12 +/- 0.09 x 10-4 cm/s in the control and treatment period, respectively. This study showed that the calculation of human in vivo permeability is based on physiological values, which are important for the wide application of these in vivo permeability data in physiologically based pharmacokinetic modeling.
authors.affiliation: Department of Surgical Sciences, University of Uppsala, Uppsala, Sweden. tina.knutson@surgsci.uu.se
authors.forename: T
authors.initials: T
authors.lastname: Knutson
authors.forename: P
authors.initials: P
authors.lastname: Fridblom
authors.forename: H
authors.initials: H
authors.lastname: Ahlström
authors.forename: A
authors.initials: A
authors.lastname: Magnusson
authors.forename: C
authors.initials: C
authors.lastname: Tannergren
authors.forename: H
authors.initials: H
authors.lastname: Lennernäs
mesh_terms: D000328:Adult; D005260:Female; D005665:Furosemide / Q000378:metabolism*; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods*; D007408:Intestinal Absorption; D007583:Jejunum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008297:Male; D009092:Mucous Membrane / Q000000981:diagnostic imaging / Q000378:metabolism; D010477:Perfusion / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D005665:Furosemide