A More Balanced Approach to Drug-Grapefruit Juice Interactions.

A more balanced approach to drug-grapefruit juice interactions.

BMJ. 2013; 346: f1073
Backman WD, Bakhai A

HubMed – drug


Increased Glucagon-like peptide-1 secretion may be involved in anti-diabetic effects of ginsenosides.

J Endocrinol. 2013 Feb 26;
Liu C, Zhang M, Hu MY, Guo HF, Li J, Yu YL, Jin S, Wang XT, Liu L, Liu XD

Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in Panax ginseng, have shown good anti-diabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP-1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its anti-diabetic effects via modulating GLP-1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI-H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 mg·kg-1 or 300 mg·kg-1) daily for four weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase of glucose-induced GLP-1 secretion and up-regulation of proglucagon mRNA expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP-1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca2+ concentration. Metabolic inhibitor azide (3 mM), KATP channel opener diazoxide (340 ?M) and Ca2+ channel blocker nifedipine (20 ?M) significantly reversed Rb1-mediated GLP-1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP-1 secretion both in vivo and in vitro. The anti-diabetic effects of ginsenosides may be a result of enhanced GLP-1 secretion. HubMed – drug


Significance of Reductive Metabolism in Human Intestine and Quantitative Prediction of Intestinal First-Pass Metabolism by Cytosolic Reductive Enzymes.

Drug Metab Dispos. 2013 Feb 26;
Nishimuta H, Nakagawa T, Nomura N, Yabuki M

The number of new drug candidates that are cleared via non-CYP enzymes has increased. However, unlike oxidation by CYP, the roles of reductive enzymes are less understood. Especially, the metabolism in intestine is not well known. The purposes of the present study were to investigate the significance of reductive metabolism in human intestine, and establish a quantitative prediction method of intestinal first-pass metabolism by cytosolic reductive enzymes, using haloperidol, mebendazole, and ziprasidone. First, we estimated the metabolic activities for these compounds in intestine and liver using subcellular fractions. Metabolic activities were detected in human intestinal cytosol (HIC) for all 3 compounds, and the intrinsic clearance values were higher than those in human liver cytosol (HLC) for haloperidol and mebendazole. These metabolic activities in HIC were NADPH- and/or NADH-dependent. Furthermore, the metabolic activities for all 3 compounds in HIC were largely inhibited by menadione, which has been used as a carbonyl reductase (CBR)-selective chemical inhibitor. Therefore, considering subcellular location, cofactor requirement, and chemical inhibition, these compounds might be metabolized by CBRs in human intestine. Subsequently, we tried to quantitatively predict intestinal availability (F(g)) for these compounds using human intestinal S9. Our prediction model using apparent permeability of parallel artificial membrane permeability assay (P(app,PAMPA)) and metabolic activities in HIS9 could predict F(g) in humans for the 3 compounds well. In conclusion, CBRs might have higher metabolic activities in human intestine than in human liver. Furthermore, our prediction method of human F(g) using HIS9 is applicable to substrates of cytosolic reductive enzymes. HubMed – drug


Cytotoxicity and uptake of archaeosomes prepared from Aeropyrum pernix lipids.

Hum Exp Toxicol. 2013 Feb 25;
Napotnik TB, Valant J, Gmajner D, Passamonti S, Miklavcic D, Ulrih NP

Archaeon Aeropyrum pernix K1 is an obligate aerobic hyperthermophilic organism with C(25,25)-archeol membrane lipids with head groups containing inositol. Interactions of archaeosomes, liposomes prepared from lipids of A. pernix, with mammalian cells in vitro were studied. In vitro cytotoxicity was tested on five different cell lines: rodent mouse melanoma cells (B16-F1) and Chinese hamster ovary (CHO) cells, and three human cell lines-epithelial colorectal adenocarcinoma cells (CACO-2), liver hepatocellular carcinoma cell line (Hep G2) and endothelial umbilical vein cell line (EA.hy926). Archaeosomes were nontoxic to human Hep G2, CACO-2 and mildly toxic to rodent CHO and B16-F1 cells but showed strong cytotoxic effect on EA.hy926 cells. Confocal microscopy revealed that archaeosomes are taken up by endocytosis. The uptake of archaeosomes and the release of loaded calcein are more prominent in EA.hy926 cells, which is in line with high toxicity toward these cells. The mechanisms of uptake, release and action in these cells as well as in vivo functioning have to be further studied for possible targeted drug delivery. HubMed – drug