Decreased absorption of midazolam in the stomach due to low pH induced by co-administration of Banha-sasim-tang.

OBJECTIVES: Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb-drug interactions and may modify the clinical safety profile of therapeutic drugs. METHODS: We investigated the potential herb-drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1ʹ-hydroxymidazolam (1ʹ-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). RESULTS: It was found that the AUC of MDZ and 1ʹ-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. CONCLUSIONS: The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.

Selective Inhibition of Bakuchicin Isolated from Psoralea corylifolia on CYP1A in Human Liver Microsomes.

Bakuchicin is a furanocoumarin isolated from Psoralea corylifolia and shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinant cDNA-expressed CYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetin O-deethylation with an IC50 value of 0.43 µM in HLMs. It was confirmed by human recombinant cDNA-expressed CYP1A1 and CYP1A2 with a K i value of 0.11 µM and 0.32 µM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs.

Green tea extract co-administered with a polymer effectively prevents alcoholic liver damage by prolonged inhibition of alcohol absorption in mice.

AIMS: Alcohol toxicity can induce multiple organ dysfunction, including the liver. Gallated catechins (GCs), the components of green tea extract (GTE), have been known to inhibit intestinal lipid absorption. This study was designed to investigate the inhibitory effect of GC on the absorption of the lipid-soluble ethanol in normal mice. In addition, the effectiveness of prolonging the GC-mediated effect was evaluated as a means of preventing alcoholic liver damage. METHODS: GTE was administered orally immediately or 90 min before ethanol administration and the blood ethanol and acetaldehyde levels were measured. Binge ethanol administration (by gavage every 6 h for 24 h) was used to induce acute liver injury, and GTE was administered 90 min prior to every ethanol administration. RESULTS: When GTE, but not GC-decreased GTE, was administered immediately before ethanol intake, the blood ethanol and acetaldehyde levels were significantly lower than those in the control. On the other hand, GTE has no effect when GTE was administered 90 min before ethanol intake. When GTE was co-administered with polyethylene glycol (PEG) or poly-γ-glutamate (PGA) 90 min before ethanol intake, the lowering effect of GTE on the blood ethanol and acetaldehyde levels was maintained in contrast to the GTE-alone-treated group. After binge ethanol administration, liver weight decreased, and serum alanine aminotransferase and aspartate aminotransferase levels were elevated. Additionally, histopathological changes, such as macrovesicular steatosis and necrosis, were induced in the liver, together with reactive oxygen species generation. When GTE + PEG or GTE + PGA, but not GTE alone, was administered 90 min before ethanol intake, acute liver injury was ameliorated. CONCLUSION: These findings support the development of GTE + PEG or GTE + PGA as an inhibitor of intestinal alcohol absorption for the preventative treatment of acute alcohol toxicity.

Glucagon-like peptide-1 protects NSC-34 motor neurons against glucosamine through Epac-mediated glucose uptake enhancement.

Bioenergetic deficits are considered a common cause of neurodegenerative diseases. Although creatine supplementation has been shown to be effective in certain neurodegenerative disorders, it is less effective in amyotrophic lateral sclerosis, a disease that primarily affects motor neurons. These neurons are particularly vulnerable to a cellular energy deficit. Using the ATP-depleting drug glucosamine, we evaluated whether the incretin hormone glucagon-like peptide (GLP)-1 protects motor neurons against glucosamine-induced cytotoxicity. Undifferentiated NSC-34 cells were differentiated into glutamate-sensitive motor neurons by a modified serum deprivation technique. Glucosamine inhibited the viability of differentiated NSC-34 cells in a time- and dose-dependent manner. Glucosamine also acutely reduced cellular glucose uptake, glucokinase activity and intracellular ATP levels. As a result, the activity of AMP-activated protein kinase as well as endoplasmic reticulum stress increased. Pretreatment with GLP-1 significantly alleviated glucosamine-mediated neurotoxicity by restoring cellular glucose uptake, glucokinase activity and intracellular ATP levels. The protective effect of GLP-1 was replicated by Exendin-4 but not Exendin-9, and not blocked by inhibitors of phosphoinositide-3 kinase, protein kinase A, cSrc, or epidermal growth factor receptor, but it was blocked by an adenylate cyclase inhibitor. A selective activator for exchange proteins directly activated by cAMP (Epac), but not a selective activator for protein kinase A, mimicked the GLP-1 effect. Therefore GLP-1 may exert its effect mainly through cAMP-dependent, Epac-mediated restoration of glucose uptake that is typically impaired by glucosamine. These findings indicate that GLP-1 could be employed therapeutically to protect motor neurons that are susceptible to bioenergetic deficits.