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Context: Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs. Objective: The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats. Materials and methods: The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally (n=6) into NASH group, evodiamine group (10mg/kg), pravastatin group (10mg/kg), and evodiamine (10mg/kg) þ pravastatin (10mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated. Results: Evodiamine decreased Cmax (159.43 ± 26.63 vs. 125.61 ± 22.17 lg/L), AUC0-t (18.17 ± 2.52 vs. 14.91 ± 2.03mg/min/L) and AUC0-1 (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1b, IL-6, and TNF-a by 27.82%, 24.76%, and 29.72% in NASH rats, respectively. Discussion and conclusions: Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans. [ABSTRACT FROM AUTHOR]

Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA ɑ-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4. Methods: Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1. Results: Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure, the Drug Effects Questionnaire (DEQ), were significant. Higher ratings by individuals with the C allele were observed on the DEQ items 'feel the alcohol effect' (P < 0.001), 'like the alcohol effect' (P < 0.001) and feel 'high' (P < 0.001). Conclusion: We did not find that the GABRG1 SNPs rs7654165 and rs6447493 moderated the effects of alcohol. Greater stimulatory and euphoric effects of alcohol in carriers of the rs279858 C allele may, in part, explain the previously reported association of this allele with AD. [ABSTRACT FROM AUTHOR]