Effects of gut microbiota on in vivo metabolism and tissue accumulation of cytochrome P450 3A metabolized drug: Midazolam

The link between drug-metabolizing enzymes and gut microbiota is well established. In particular, hepatic cytochrome P450 (CYP) 3A activities are presumed to be affected by gut microbiota. However, there is no direct evidence that the gut microbiota affects CYP3A metabolism or the clearance of clinically relevant drugs in vivo. Our purpose was to evaluate the effects of gut microbiota on in vitro and in vivo drug metabolism and on the clearance of midazolam, which is a standard CYP3A metabolized drug. Hepatic Cyp3a activity and in vitro midazolam hydroxylase activity were compared using specific pathogen-free (SPF) and germ-free (GF) mice. In a pharmacokinetics (PK) study, SPF and GF mice were intraperitoneally injected with 60 mg/kg of midazolam, and plasma and tissue concentrations were measured. Hepatic Cyp3a activity and midazolam hydroxylase activity were significantly lower in GF mice than in SPF mice. Notably, in the PK study, the area under the plasma concentration–time curve from time zero to infinity and the elimination half-life were approximately four-fold higher in GF mice compared with SPF mice. Furthermore, the concentration of midazolam in the brain 180 min after administration was about 14-fold higher in GF mice compared with SPF mice. Together, our results demonstrated that the gut microbiota altered the metabolic ability of Cyp3a and the tissue accumulation of midazolam.     

Host microbiota dictates the proinflammatory impact of LPS in the murine liver

Gut microbiota can impact liver disease development via the gut-liver axis. Liver inflammation is a shared pathological event in various liver diseases and gut microbiota might influence this pathological process. In this study, we studied the influence of gut microbiota on the inflammatory response of the liver to lipopolysaccharide (LPS). The inflammatory response to LPS (1–10 μg/ml) of livers of specific-pathogen-free (SPF) or germ-free (GF) mice was evaluated ex vivo, using precision-cut liver slices (PCLS). LPS induced a more pronounced inflammatory response in GF PCLS than in SPF PCLS. Baseline TNF-α gene expression was significantly higher in GF slices as compared to SPF slices. LPS treatment induced TNF-α, IL-1β, IL-6 and iNOS expression in both SPF and GF PCLS, but the increase was more intense in GF slices. The anti-inflammatory markers SOCS3 and IRAK-M gene expression was significantly higher in GF PCLS than SPF PCLS at 24h with 1 µg/ml LPS treatment, and IL-10 was not differently expressed in GF PCLS than SPF PCLS. In addition, TLR-4 mRNA, but not protein, at basal level was higher in GF slices than in SPF slices. Taken together, this study shows that, in mice, the host microbiota attenuates the pro-inflammatory impact of LPS in the liver, indicating a positive role of the gut microbiota on the immune homeostasis of the liver.     

Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids

The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5).KEY WORDS: Bile acids, Liver, Intestine, Transporters, Lipid metabolism, Energy homeostasisAbbreviations: ACCII, acetyl-CoA carboxylase 2; APO, apolipoproteins; ASBT, apical sodium-dependent bile acid transporter; BSEP, bile salt export pump; CYP7A1, cholesterol 7α-hydroxylase; DIO2, deiodinase 2; FAS, fatty acid synthase; FGF, fibroblast growth factor; FOXO1, forkhead box protein O1; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X-receptor; G6Pase, glucose-6-phosphatase; GLP-1, glucagon-like polypeptide-1; HNF4α, hepatocyte nuclear factor 4 alpha; IBABP, ileal bile acid binding protein; LDL, low density lipoprotein; NTCP, Na⁺-taurocholate transporting polypeptide; OATP, organic anion transporting polypeptide; OST, organic solute transporter; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PPAR, peroxisome proliferator-activated receptor; SHP, small heterodimer partner; SREBP1c, sterol regulatory element binding protein-1c; T4, thyroid hormone; TGR5, G-protein-coupled bile acid receptor; VLDL, very low density lipoprotein     

Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism

The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism.Key words: Bile acid, Sphingosine-1 phosphate receptor, Heptic lipid metabolismAbbreviations: ABC, ATP-binding cassette; AKT/PKB, protein kinase B; BSEP/ABCB11, bile salt export protein; CA, cholic acid; CBA, conjugated bile acids; CDCA, chenodeoxycholic acid; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, 12α-hydroxylase; DCA, deoxycholic acid; EGFR, epidermal growth factor receptor; ERK, extracellular regulated protein kinases; FGF15/19, fibroblast growth factor 15/19; FGFR, fibroblast growth factor receptor; FXR, farnesoid X receptor; G-6-Pase, glucose-6-phophatase; GPCR, G-protein coupled receptor; HDL, high density lipoprotein; HNF4α, hepatocyte nuclear factor-4α; IBAT, ileal sodium-dependent bile acid transporter; JNK1/2, c-Jun N-terminal kinase; LCA, lithocholic acid; LDL, low-density lipoprotein; LRH-1, liver-related homolog-1; M1–5, muscarinic receptor 1–5; MMP, matrix metalloproteinase; NAFLD, non-alcoholic fatty liver disease; NK, natural killer cells; NTCP, sodium taurocholate cotransporting polypeptide; PEPCK, PEP carboxykinse; PTX, pertussis toxin; S1P, sphingosine-1-phosphate; S1PR2, sphingosine-1-phosphate receptor 2; SHP, small heterodimer partner; SphK, sphingosine kinase; SPL, S1P lyase; Spns2, spinster homologue 2; SPPs, S1P phosphatases; SRC, proto-oncogene tyrosine-protein kinase; TCA, taurocholate; TGR5, G-protein-coupled bile acid receptor; TNFα, tumor necrosis factor α; VLDL, very-low-density lipoprotein     

The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics

The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans, accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an “endocrine organ” with potential to alter host physiology, perhaps to their own favor. We propose the term “sterolbiome” to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed.Abbreviations: APC, adenomatous polyposis coli; BA, bile acids; BSH, bile salt hydrolases; CA, cholic acid; CDCA, chenodeoxycholic acid; COX-2, cyclooxygenase-2; CRC, colorectal cancer; CYP27A1, sterol-27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; DCA, deoxycholic acid; EGFR, epidermal growth factor receptor; FAP, familial adenomatous polyposis; FGF15/19, fibroblast growth factor 15/19; FXR, farnesoid X receptor; GABA, γ-aminobutyric acid; GPCR, G-protein coupled receptors; HMP, Human Microbiome Project; HSDH, hydroxysteroid dehydrogenase; LCA, lithocholic acid; LOX, lipooxygenase; MetaHIT, Metagenomics of the Human Intestinal Tract; NSAIDs, non-steroidal anti-inflammatory drugs; PKC, protein kinase C; PSC, primary sclerosing cholangitis; PXR, pregnane X receptor; UDCA, ursodeoxycholic acid; VDR, vitamin D receptorKEY WORDS: Sterolbiome, Gut microbiome, Bile acids, Metabolite, Therapeutic agent     

Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry.

Berberine (Ber) and its main metabolites were identified and quantified using liquid chromatography/electrospray ionization/ion trap mass spectrometry. Rat plasma contained the main metabolites, berberrubine, thalifendine, demethyleneberberine, and jatrorrhizine, as free and glucuronide conjugates after p.o. Ber administration. Moreover, the original drug, the four main metabolites, and their glucuronide conjugates were all detected in liver tissues after 0.5 h and in bile samples 1 h after p.o. Ber administration. Therefore, the metabolic site seemed to be the liver, and the metabolites and conjugates were evidently excreted into the duodenum as bile. The pharmacokinetics of Ber and the four metabolites were determined in conventional and pseudo germ-free rats (treated with antibiotics) after p.o. administration with 40 mg/kg Ber. The AUC0-limt and mean transit time values of the metabolites significantly differed between conventional and pseudo germ-free rats. The amounts of metabolites were remarkably reduced in the pseudo germ-free rats, whereas levels of Ber did not obviously differ between the two groups. The intestinal flora did not exert significant metabolic activity against Ber and its metabolites, but it played a significant role in the enterohepatic circulation of metabolites. In this sense, the liver and intestinal bacteria participate in the metabolism and disposition of Ber in vivo.     

Intestinal microbiota-mediated biotransformations alter the pharmacokinetics of the major metabolites of azathioprine in rats after oral administration

Adverse reactions to azathioprine (AZA) vary greatly among individuals, which is associated with the variable levels of its major metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). The intestinal microbiota has been proven to contain AZA-metabolizing enzymes, although the explicit role of the intestinal microbiota in AZA metabolism in vivo remains poorly comprehended. In this study, the pharmacokinetic behaviours of 6-TGN and 6-MMP were assessed in the pseudo germ-free (PGF) group and control group following oral administration of AZA. The AUC_0-t and C_max of 6-TGN in the PGF group were significantly decreased by 34.0% and 35.0% (P < 0.05) compared with those in the control group. Additionally, the AUC_0-t and C_max of 6-MMP were reduced by 27.9% and 34.2% in the PGF group, although the differences were not significant. The TPMT and NUDT15 genotypes of rats in the two groups were genetically identical. The expression levels of key AZA-metabolizing enzymes in liver were not different between two groups. Furthermore, the major metabolites of AZA in the incubation system with intestinal microbial enzymes were identified. In summary, shifts in the composition of the intestinal microbiota may regulate the exposure of 6-TGN in vivo by altering the gut microbial metabolism of AZA.     

Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats.

We have investigated the metabolism of isoflavones and lignans in germ-free (GF) rats and rats associated with human faecal bacteria (human flora associated [HFA] rats), in order to provide unequivocal evidence for the role of the gut microflora in the absorption and metabolism of these phytoestrogens. Furthermore, we have investigated whether certain metabolic characteristics (high equol-producing and low equol-producing status) of human intestinal floras can be transferred to GF rats. Germ-free rats fed a soy-isoflavone containing diet excreted large quantities of daidzein and genistein in urine indicating that the gut microflora is not required for the absorption of isoflavones. The isoflavone metabolites equol, O-desmethylangolensin and the lignan enterolactone were not detectable in urine from the GF rats, but were present in HFA rat urine, indicating that they were products of gut microflora activity. Colonization of GF rats with a faecal flora from a human subject with the capacity to convert daidzein to equol, resulted in the rats excreting substantial amounts of the metabolite. In contrast, equol was undetectable in urine of HFA rats associated with a faecal flora from a low equol-producing subject. The results therefore show that the inability of some subjects to produce equol is a consequence of the lack of specific components of the gut microflora.     

Intestinal microbiota and obesity

The human gut harbors a highly diverse microbial ecosystem of approximately 400 different species, which is characterized by a high interindividual variability. The intestinal microbiota has recently been suggested to contribute to the development of obesity and the metabolic syndrome. Transplantation of gut microbiota from obese mice to nonobese, germ-free mice resulted in transfer of metabolic syndrome-associated features from the donor to the recipient. Proposed mechanisms for the role of gut microbiota include the provision of additional energy by the conversion of dietary fiber to short-chain fatty acids, effects on gut-hormone production, and increased intestinal permeability causing elevated systemic levels of lipopolysaccharides (LPS). This metabolic endotoxemia is suggested to contribute to low-grade inflammation, a characteristic trait of obesity and the metabolic syndrome. Finally, activation of the endocannabinoid system by LPS and/or high-fat diets is discussed as another causal factor. In conclusion, there is ample evidence for a role of gut microbiota in the development of obesity in rodents. However, the magnitude of its contribution to human obesity is still unknown.     

胆汁酸-肠道菌群轴在2型糖尿病中的作用

目的 分析2型糖尿病(type 2 diabetes mellitus,T2DM)患者和正常人群胆汁酸与肠道菌群差异,探讨胆汁酸-肠道菌群轴在T2DM中的作用。方法 利用代谢组学、16S rRNA测序手段分别对T2DM患者中的血清胆汁酸含量及粪便肠道微生物进行检测及分析,结合斯皮尔曼相关性分析,明确胆汁酸-肠道菌群在T2DM中的代谢对话关系。结果 血清胆汁酸含量和肠道微生物的丰度在T2DM患者与正常人群中存在一定的差异。与正常人群相比,甘氨熊脱氧胆酸、牛磺鹅脱氧胆酸、甘氨鹅脱氧胆酸的含量在T2DM患者中显著降低;T2DM患者中肺炎克雷伯菌属、普拉梭菌属的相对丰度较正常人群明显升高,而狄氏副拟杆菌属、普雷沃菌属、艾克曼菌属、双歧杆菌属的相对丰度明显降低;斯皮尔曼相关性分析表明甘氨熊脱氧胆酸与狄氏副拟杆菌属、艾克曼菌属呈正相关,与克雷伯氏菌属呈负相关。结论 胆汁酸-肠道菌群轴是维持机体稳态的必要因素,在T2DM中发挥重要作用。     

肠道菌群在中草药抗溃疡性结肠炎中的作用

溃疡性结肠炎(ulcerative colitis,UC)是一种慢性非特异性炎症性肠病,病情迁延难愈,且易反复发作,被世界卫生组织列为现代难治性疾病.UC的发病机制与肠道菌群失调密切相关.肠道菌群与胆汁酸、短链脂肪酸和色氨酸等代谢,与免疫系统以及肠黏膜屏障等的相互作用均影响UC的发生和发展.中草药活性成分、单味中草药及...     

Role of the intestinal microflora in clonazepam metabolism in the rat

1. The metabolism of clonazepam was studied in vitro and in vivo using germ-free and ex-germ-free rats.

2. Incubation of clonazepam with rat-intestinal lumen contents gave nearly complete reduction of clonazepam to 7-aminoclonazepam. Rat-hepatic microsomes also reduced clonazepam but only under anaerobic conditions. Aerobic microsomal incubations gave 3-hydroxyclonazepam as the predominant metabolite. Both aerobic and anaerobic microsomal metabolism were induced by phenobarbital. Carbamazepine pretreatment significantly induced only 3-hydroxylation slightly; whereas β-naphthoflavone had no significant effect.

3. Extensive biliary disposition of hydroxylated clonazepam metabolites into the gut occurred. Only very low levels of clonazepam were found in bile. Using a linked-rat procedure enterohepatic recirculation of biliary metabolites was demonstrated and suppression (antibiotic treatment) or absence (germ-free) of the gut microflora nearly eliminated recycling.

4. Following oral administration of [¹⁴C]clonazepam to germ-free rats, reduced metabolites accounted for 15% of the radioactivity in the urine, with over 70% of the ¹⁴C attributed to a phenolic clonazepam metabolite. In contrast 77% of the recovered metabolites were derived from nitroreduction in the same animals following acquisition of an intestinal microflora; 7-acetamidoclonazepam was the major metabolite in these ex-germ-free animals. These studues show that clonazepam metabolism is primarily reductive in the presence of gut flora and oxidative in its absence.     

Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia

The progression of hyperuricemia disease is often accompanied by damage to renal function. However, there are few studies on hyperuricemia nephropathy, especially its association with intestinal flora. This study combines metabolomics and gut microbiota diversity analysis to explore metabolic changes using a rat model as well as the changes in intestinal flora composition. The results showed that amino acid metabolism was disturbed with serine, glutamate and glutamine being downregulated whilst glycine, hydroxyproline and alanine being upregulated. The combined glycine, serine and glutamate could predict hyperuricemia nephropathy with an area under the curve of 1.00. Imbalanced intestinal flora was also observed. Flavobacterium, Myroides, Corynebacterium, Alcaligenaceae, Oligella and other conditional pathogens increased significantly in the model group, while Blautia and Roseburia, the short-chain fatty acid producing bacteria, declined greatly. At phylum, family and genus levels, disordered nitrogen circulation in gut microbiota was detected. In the model group, the uric acid decomposition pathway was enhanced with reinforced urea liver-intestine circulation. The results implied that the intestinal flora play a vital role in the pathogenesis of hyperuricemia nephropathy. Hence, modulation of gut microbiota or targeting at metabolic enzymes, i.e., urease, could assist the treatment and prevention of this disease.     

Enhancement of cholesterol turnover in rats by a catatoxic steroid (PCN) and a bile acid sequestrant (colestipol-HCl)

Catatoxic steroids induce hepatic microsomal enzymes. To determine if cholesterol catabolism to bile acids by microsomal enzymes is stimulated by a catatoxic steroid, effects of pregnenolone-16α-carbonitrile (PCN) alone or with colestipol-HCl on cholesterol 7α-hydroxylase, cholesterol synthesis and cholesterol turnover were studied. Male rats fed diets containing colestipol (1%), PCN (0.085%), colestipol plus PCN, or basic diet were injected with [1,2,-³H]-cholesterol complexed with serum lipoproteins. Serum cholesterol specific radioactivity was measured for 49 days. Hepatic cholesterol and bile acid synthesis were estimated by [1-¹⁴C]-acetate incorporation and cholesterol 7α-hydroxylase activity. Turnover curves were analyzed using a three-pool model. PCN significantly increased all rate constants and cholesterol production rate (10.75 to 12.87 mg/day), which in this model is a measure of total body cholesterol turnover. Colestipol significantly increased total body cholesterol turnover (10.75 to 19.91 mg/day) and the excretion rate constant (0.44 to 0.88 day^?1) and increased acetate incorporation 6-fold and cholesterol 7α-hydroxylase activity 2-fold. PCN only slightly inhibited the latter. Effects of colestipol plus PCN were not different from those of colestipol alone. No treatment significantly changed cholesterol serum levels overall. Colestipol results are consistent with reported data for bile acid sequestrants. PCN markedly increased cholesterol flux between pools; it does not appear to induce and may, in fact, inhibit bile acid synthesis, perhaps by decreasing availability of necessary cofactors or cholesterol substrate.     

Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats

To evaluate the metabolic interaction between host and gut microflora on drug metabolism, pseudo germ‐free rats were prepared with an antibiotics cocktail to change their gut conditions. The usefulness of the pseudo germ‐free model was evaluated for observing the DMPK of acetaminophen (APAP). Pseudo germ‐free rats were prepared by orally administering antibiotic cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered to control and pseudo germ‐free rats. The plasma concentration of APAP and its six metabolites were quantified using a validated LC‐MS/MS method. A non‐compartment model estimated the pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve (AUC; AUC_metabolite/AUC_APAP) were also observed to evaluate the change of APAP metabolism. The AUCs of APAP and APAP‐Glth (glutathione) were higher and the AUC_APAP‐Sul/AUC_APAP (metabolic efficiency of sulfate conjugation) was lower in pseudo germ‐free rats than those in the control rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction of the sulphate supply, causing an increase of the AUC of APAP and APAP‐Glth. The activities of gut microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic APAP metabolism. These results indicate that gut microflora may play an important role in the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and gut microflora should be considered upon drug administration and pseudo germ‐free rats prepared in the present study can be competent for investigating the metabolic interaction between host and gut microflora on drug metabolism. Copyright © 2012 John Wiley & Sons, Ltd.     

Interactions of gut microbiota with functional food components and nutraceuticals

The human gut is populated by an array of bacterial species, which develop important metabolic and immune functions, with a marked effect on the nutritional and health status of the host. Dietary component also play beneficial roles beyond basic nutrition, leading to the development of the functional food concept and nutraceuticals. Prebiotics, polyunsaturated fatty acids (PUFAs) and phytochemicals are the most well characterized dietary bioactive compounds. The beneficial effects of prebiotics mainly relay on their influence on the gut microbiota composition and their ability to generate fermentation products (short-chain fatty acids) with diverse biological roles. PUFAs include the ω-3 and ω-6 fatty acids, whose balance may influence diverse aspects of immunity and metabolism. Moreover, interactions between PUFAs and components of the gut microbiota may also influence their biological roles. Phytochemicals are bioactive non-nutrient plant compounds, which have raised interest because of their potential effects as antioxidants, antiestrogenics, anti-inflammatory, immunomodulatory, and anticarcinogenics. However, the bioavailability and effects of polyphenols greatly depend on their transformation by components of the gut microbiota. Phytochemicals and their metabolic products may also inhibit pathogenic bacteria while stimulate the growth of beneficial bacteria, exerting prebiotic-like effects. Therefore, the intestinal microbiota is both a target for nutritional intervention and a factor influencing the biological activity of other food compounds acquired orally. This review focuses on the reciprocal interactions between the gut microbiota and functional food components, and the consequences of these interactions on human health.     

肠道菌群代谢药物研究进展

长期以来,由于肠道菌群本身的复杂性以及培养方法和分析技术的限制,肠道菌群在药物代谢和体内处置中的作用未得到应有的重视。近年来,随着技术的快速发展,围绕肠道菌群的大量研究将对肠道菌代谢和肠道菌-宿主共代谢的认识提高到前所未有的深度。肠道菌群不仅能够直接代谢许多药物,还通过宿主、菌群、药物之间复杂多维的相互作用间接改变药物代谢,从而影响个体对药物治疗的响应(效应、毒性、耐药性等)。肠道菌群结构及代谢功能受多种因素的影响。综述近期肠道菌群代谢药物研究领域的重要进展及研究趋势,以期推进精准治疗,促进药物发现及新的治疗策略的出现。     

Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine

Quinidine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48?h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethylmethoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (r _s?=??0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethylchlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (α?=?0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.