Ansamycins are hypolipidemic compounds which, when administered to various animal species, dramatically lower high density lipoprotein (HDL) cholesterol levels, in addition to reducing the levels of other lipoprotein classes. The current study tested one of these ansamycins (CGP 43371) for its hypolipidemic and anti-atherosclerotic activity in cholesterol-fed rabbits. Rabbits were fed a 0.25% cholesterol-enriched diet with or without admixed CGP 43371, equivalent to 30 mg/kg per day for 16 weeks. Compared with control rabbits, CGP 43371 treatment lowered total cholesterol levels (46%, P<0.05) and lipoprotein cholesterol levels (HDL, 58%; VLDL, 49% [both P<0.05]; LDL, 28% [not significant]). Despite the dramatic lowering of HDL cholesterol levels, aortic atherosclerosis, assessed by grossly visible sudanophilia, was significantly inhibited versus controls (total aorta=38%; aortic arch=32%; thoracic aorta=60%). Of particular note in CGP 43371-treated rabbits was a striking splenomegaly, which correlated with the presence of massive accumulations of macrophage foam cells in the splenic red pulp. We speculate that CGP 43371 inhibits the development of atheroselerotic lesions in rabbits by both a hypolipidemic mechanism, and by a mechanism(s) in which macrophage foam cells accumulate in the spleen.

1996-03-01·The Journal of Clinical Pharmacology3区 · 医学

Explaining Variable Absorption of a Hypolipidemic Agent (CGP 43371) in Healthy Subjects by Gamma Scintigraphy and Pharmacokinetics

3区 · 医学

Article

作者: U. Yun Ryo ; Brian Walter ; Erik P. Sandefer ; Jim X. Sun ; Richard C. Page ; Alexandra Cipriano ; Keith Chan ; Wieslawa M. Maniara ; Mark L. Powell ; George A. Digenis

The gastrointestinal absorption of a hypolipidemic agent (CGP 43371) was investigated using an external scintigraphy technique in six healthy men. After an overnight fast, subjects received a single 800‐mg oral dose of CGP 43371 (4 capsules of 200 mg each) and one capsule of radioactive samarium‐153 oxide (100–130 μCi) as a nonabsorbable marker of gastrointestinal transit and fecal recovery for CGP 43371. In vivo gastrointestinal transit of samarium‐153 was monitored via gamma scintigraphy for 48 hours after administration to coincide with blood sampling. Samarium‐153 content in whole fecal samples was determined by external gamma scintigraphy, and CGP 43371 content in both fecal and plasma samples was determined using high‐performance liquid chromatography (HPLC). The results of fecal analysis indicated that transit of the two compounds in the gastrointestinal tract were similar, and bioavailability of CGP 43371 was calculated to be 9% based on the difference between the cumulative amounts of the nonabsorbable radioactive marker and CGP 43371 found in the feces. The onset of drug absorption occurred 4 hours after administration when radioactive samarium‐153 was in the distal small bowel, and peak plasma drug level occurred 6 hours after administration, which corresponded with the arrival of samarium‐153 in the terminal ileum and ileal/cecal junction. This observation supported the concept that primary absorption of this compound was in the distal to terminal portion of the ileum. Although the onset of drug absorption was delayed, it was curious that the rate of gastric emptying also affected the extent of absorption. A positive correlation (r = 0.91) between area under the drug curve (AUC) and area under the transit curve (AUTC) of the gastric emptying showed that longer gastric residence improved oral absorption of CGP 43371.

1995-01-06·Atherosclerosis2区 · 医学

The ansamycins: a novel class of hypolipidemic agents with a high affinity for lipoproteins

2区 · 医学

Article

作者: Warren H. Lee ; Zouhair F. Stephan ; Joyce C. Gibson

The ansamycins are derivatives of 3-piperazino rifamycin with potent hypolipidemic activity in nonprimate and primate species. Since the cholesterol reduction results from increased uptake and catabolism of lipoprotein cholesterol, it was hypothesized that the hydrophobicity of the ansamycins could result in a lipoprotein association which facilitates clearance. When radiolabeled ansamycins CGP 43371 or CGS 24565 were incubated with human plasma, > 95% was lipoprotein-bound up to drug levels of 25 microM. With plasma from chow-fed rats, radiolabeled compounds again distributed with the lipoproteins. Feeding a cholesterol/cholic acid diet to rats shifted the cholesterol distribution to lower density lipoproteins and in vitro incubation resulted in a shift of radiolabeled drug to lower density lipoproteins as well. Intravenous administration of radiolabeled ansamycins to chow-fed or cholesterol-fed rats resulted in a plasma lipoprotein binding profile indistinguishable from the corresponding in vitro incubations. When [14C]-CGP 43371 bound in vitro to high density lipoprotein (HDL) was reincubated with increasing concentrations of low density lipoprotein (LDL), a concentration-dependent fall in HDL association and increase in LDL binding was observed. Thus, the ansamycins have a high affinity for all plasma lipoproteins and can transfer between lipoprotein fractions. When [125I]-labeled LDL or HDL was incubated with CGP 43371 and Hep G2 cells, the cell association of the 125I label was significantly increased in a dose-dependent manner. In addition, plasma clearance of [14C]cholesterol oleate-labeled HDL coinjected with CGP 43371 was accelerated relative to control rats and radioactivity was specifically increased in livers of CGP 43371-treated rats. The physical association of the ansamycins with lipoproteins may thus lead to subtle conformational changes and enhanced hepatic uptake.

100 项与 CGP-43371 相关的药物交易

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