Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat Hydrolysis of glucuronic acid conjugates in the gut lumen

ABSTRACT:This study describes the in vitro metabolism of [ 14 C]dasatinib in liver tissue incubations from rat, monkey, and human and the in vivo metabolism in rat and monkey. Across species, dasatinib underwent in vitro oxidative metabolism to form five primary oxidative metabolites. In addition to the primary metabolites, secondary metabolites formed from combinations of the oxidative pathways and conjugated metabolites of dasatinib and its oxidative metabolites were also observed in hepatocytes incubations. In in vivo studies in rats and monkeys, the majority of the radioactive dose was excreted in the bile and feces. In bile duct-cannulated monkeys after an i.v. dose, 13.7% of the radioactive dose was excreted in the feces through direct secretion. Dasatinib comprised 56 and 26% of the area under the curve (AUC) (0-8 h) of total radioactivity (TRA) in plasma, whereas multiple metabolites accounted for the remaining 44 and 74% of the AUC (0-8 h) of TRA for rats and monkeys, respectively. In rat and monkey bile, dasatinib accounted for <12% of the excreted dose, suggesting that dasatinib was extensively metabolized before elimination. The metabolic profiles in bile were similar to the hepatocyte profiles. In both species, a large portion of the radioactivity excreted in bile (>29% of the dose) was attributed to N-oxides and conjugated metabolites. In rat and monkey feces, only the oxidative metabolites and their further oxidation products were identified. The absence of conjugative or N-oxide metabolites in the feces suggests hydrolysis or reduction, respectively, in the gastrointestinal tract before elimination.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Biotransformation of [¹⁴C]Dasatinib: In Vitro Studies in Rat, Monkey, and Human and Disposition after Administration to Rats and Monkeys

Christopher¹,

Cui²,

Li³

et al. 2008

“…4; Table 3). The difference in the bile and fecal profiles was attributed to hydrolysis of the conjugative metabolites in the gastrointestinal tract before excretion in the feces (Parker et al, 1980;Christopher et al, 2008). M6, which was FIG.…”

Section: Discussionmentioning

confidence: 99%

“…It has been known that glucuronides typically undergo hydrolysis in the gastrointestinal tract by gut flora before excretion in the feces (Parker et al, 1980;Christopher et al, 2008). Therefore, the current studies included administration of […”

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confidence: 99%

Metabolism and Disposition of [¹⁴C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Hong

Su²,

Sun³

et al. 2010

]BMS-690514 to rats and dogs, the majority of the radioactive dose (61-71%) was recovered in the feces, whereas 18 to 20% was eliminated in urine. In bile duct-cannulated rats, 83 and 17% of the administered radioactivity was recovered in the bile and urine, respectively, suggesting that biliary secretion was a major route for the elimination of BMS-690514-derived radioactivity in rats.The parent compound underwent extensive metabolism in both species, with <12% of the administered radioactivity recovered as BMS-690514 in the excreta samples. Metabolite profiles in plasma were qualitatively similar in rats, rabbits, and dogs. Unchanged BMS-690514 was a prominent drug-related component in the plasma profiles from all the species. However, multiple metabolites contributed significantly to the circulating radioactivity, particularly for rabbit and dog, in which metabolites comprised 73 to 93% of the area under the time curve (0-8 h). Circulating metabolites included M6, a direct Oglucuronide conjugate; M1, a hydroxylated metabolite; and glucuronide conjugates of hydroxylated and O-demethylated metabolites. Overall, the results from these studies suggested that BMS-690514 was well absorbed and highly metabolized through multiple pathways in these preclinical species.

“…These differences could best be explained by an enterohepatic circulation process of biliary excretion of the glucuronides of muraglitazar and its metabolites, hydrolysis of the glucuronides by bacterial ␤-glucuronidase, and reabsorption of the aglycones, followed by further metabolism before the oxidative metabolites were finally excreted into feces. The above discussion suggested a low level of enterohepatic circulation of muraglitazar compared with other carboxylic acid-containing drugs (Parker et al, 1980;Pollack and Brouwer, 1991;Tabata et al, 1995).…”

Section: Downloaded Frommentioning

confidence: 99%

GLUCURONIDATION AS A MAJOR METABOLIC CLEARANCE PATHWAY OF ¹⁴C-LABELED MURAGLITAZAR IN HUMANS: METABOLIC PROFILES IN SUBJECTS WITH OR WITHOUT BILE COLLECTION

Wang

Zhang²,

Swaminathan³

et al. 2005

ABSTRACT:The metabolism and disposition of 14 C-labeled muraglitazar (Pargluva), a novel dual ␣/␥ peroxisome proliferator-activated receptor activator, was investigated in eight healthy male subjects with and without bile collection (groups 1 and 2) after a single 20-mg oral dose. Bile samples were collected for 3 to 8 h after dosing from group 2 subjects in addition to the urine and feces collection. In plasma, the parent compound was the major component, and circulating metabolites, including several glucuronide conjugates, were minor components at all time points. The exposure to parent drug (C max and area under the plasma concentration versus time curve) in subjects with bile collection was generally lower than that in subjects without bile collection. The major portion of the radioactive dose was recovered in feces (91% for group 1 and 51% for group 2). In addition, 40% of the dose was recovered in the bile from group 2 subjects. In this 3-to 8-h bile, the glucuronide of muraglitazar (M13, 15% of dose) and the glucuronides of its oxidative metabolites (M17a,b,c, M18a,b,c, and M20, together, 16% of dose) accounted for approximately 80% of the biliary radioactivity; muraglitazar and its O-demethylated metabolite (M15) each accounted for approximately 4% of the dose. In contrast, fecal samples only contained muraglitazar and its oxidative metabolites, suggesting hydrolysis of biliary glucuronides in the intestine before fecal excretion. Thus, the subjects with and without bile collection showed different metabolic profiles of muraglitazar after oral administration, and glucuronidation was not observed as a major pathway of metabolic clearance from subjects with the conventional urine and fecal collection, but was found as a major elimination pathway from subjects with bile collection.Peroxisome proliferator-activated receptors (PPARs) are a set of nuclear hormone receptors (comprising the ␣, ␥, and ␦ subtypes) which act as transcription factors in the regulation of multiple genes involved in such diverse disease areas as type 2 diabetes, dyslipidemia, obesity, inflammation, cancer, and osteoporosis (Torra et al., 2001;Taskinen, 2003;Yajima et al., 2004). The two most intensively investigated subtypes have been PPAR␣ (primarily expressed in the liver and which plays a critical role in lipid metabolism) and PPAR␥ (predominantly expressed in adipose tissue and implicated in insulin sensitization as well as glucose and fatty acid utilization). PPAR␣ is the target of the fibrate class of hypolipidemic drugs such as fenofibrate (Balfour et al., 1990;Despres, 2001;Packard et al., 2002) and gemfibrozil (Spencer and Barradell, 1996), whereas PPAR␥ is the target of the thiazolidinedione (Mudaliar and Henry, 2001) class of antidiabetic drugs such as rosiglitazone (Balfour and Plosker, 1999;Cheng-Lai and Levine, 2000;Goldstein, 2000) and pioglitazone (Gillies and Dunn, 2000).glycine, is a novel dual ␣/␥ PPAR activator, and the structure of muraglitazar is shown in Fig. 1. It has been shown that muraglitazar has both gluc...