Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

Glomerular permselectivity characteristics were studied in the Sprague-Dawley rat in vivo and in the isolated rat kidney perfused with an erythrocyte-free Krebs-Henseleit buffered 5% albumin solution (IPK). IPK permselectivity in vitro, assessed by fractional clearances of neutral dextran (FCND) and dextran sulfate (FCDS) with molecular radii 18-43 A, was essentially similar to that of the Sprague-Dawley rat in vivo. The negative charge barrier of the IPK glomerular filter was intact [e.g., FCND of 36 A = 0.10 +/- 0.01 (SE) vs. FCDS of 36 A = 0.01 +/- 0.00 (P less than 0.01)]. Dextrans of an intermediate size (26-34 A) had lower fractional clearances in the IPK than in vivo [e.g., FCND of 30 A in IPK = 0.23 +/- .04 vs. FCND of 30 A in vivo 0.40 +/- 0.01 (P less than 0.01)]. This decreased clearance of dextrans of an intermediate molecular size is predicted by pore theory, since the IPK has an increased afferent glomerular plasma flow rate. As glomerular permselectivity characteristics in the IPK simulate in vivo characteristics, such preparations are suitable in vitro models in which to study factors that modulate permselectivity. The demonstration that the glomerular filter in the IPK has a normal negative charge barrier indicates that the increased protein excretion in IPK systems cannot be attributed to abnormalities of this component of the filtration barrier.

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Precision-Cut Rat Liver Slices in Dynamic Organ Culture for Structure-Toxicity Studies

Journal of the American College of Toxicology ◽

10.3109/10915819009078767 ◽

1990 ◽

Vol 9 (6) ◽

pp. 621-627 ◽

Cited By ~ 5

Author(s):

Klaus Brendel ◽

Robyn L. Fisher ◽

Carlos L. Krumdieck ◽

A. Jay Gandolfi

Keyword(s):

Fatty Acids ◽

Organ Culture ◽

Chain Length ◽

Rat Liver ◽

Sprague Dawley ◽

Toxicity Studies ◽

Liver Slices ◽

Sprague Dawley Rat ◽

Branched Chain

We describe a novel in vitro mammalian liver system, which simplifies both metabolism and hepatotoxicity studies in a multitude of species. This system is based on mechanical cutting of slices with high precision and culture of such slices under dynamic organ culture conditions. This system permits study of intoxication or metabolism for many hours to days and is suitable for integrative biochemical assays as well as histological and morphological evaluation. We report the toxicity exhibited by the isomeric dichlorobenzenes, which in Sprague-Dawley rat liver slices is M>O>P. We also compared a series of bromobenzene analogs, which in Sprague-Dawley rat liver slices are toxic in the following sequence DBB > BB > BBN > BA > BBT > BT. The toxicity of medium chain length branched-chain fatty acids related to valproic acid also was evaluated in this system. Results show that toxicity increased with chain length in α-methyl fatty acids and depended on the location of the carboxyl group in branched-chain octanoic acids. These examples serve to illustrate the utility of precision-cut rat liver slices in dynamic organ culture for structure—toxicity studies.

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