Are you Trent L Abraham?

Claim your profile

Publications (4)12.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabolism and disposition of LY 368842, a beta 3-adrenergic receptor agonist, were characterized in F344 rats following oral or intravenous administration of [(14)C]LY 368842. These studies were conducted as part of the investigation of the mechanism of dark liver pigmentation in LY 368842-treated F344 rats. The maximum plasma concentration of LY 368842 was reached at 3 h after an oral dose, with an elimination half-life of 4 h. The oral bioavailability of LY 368842 was determined as 8%. A tissue distribution study by quantitative whole-body autoradiography indicated high concentrations of radiocarbon in gastrointestinal contents and moderate concentrations in liver. The radiocarbon was rapidly eliminated in rats, with approximately 3% of the dose recovered in urine and 90% in faeces over 168 h. In bile duct-cannulated rats, about 42% of the dose was recovered in bile and 41% remained in the faeces. Metabolites of LY 368842 were identified in rat urine, faeces, bile and plasma samples. Oxidative metabolism of LY 368842 led to the formation of a hydroxy metabolite, an indole-2,3-dione metabolite and oxidative cleavage products such as amine and diol metabolites. Several glucuronide conjugates were also identified in rat bile. These data suggest that LY 368842 is not completely absorbed but is widely distributed, extensively metabolized and rapidly eliminated in rats after oral administration.
    Xenobiotica 07/2005; 35(6):647-60. DOI:10.1080/00498250500187992 · 2.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dark liver pigmentation was observed in F344 rats in a subchronic toxicology study after daily dosing of LY368842 glycolate. In addition, green-colored urine was observed in some animals. To identify the source of the pigment and its potential for toxic consequences, the liver pigment was isolated from the liver tissue of rats. The resulting material was a dark brown to black powder that was insoluble in water, organic solvents, or a tissue-solubilizing agent. Several techniques, such as chemical degradation, HPLC, tandem mass spectrometry (LC/MS/MS), (1)H NMR, and matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), were employed to characterize the dark liver pigment. Following oxidative degradation of the isolated pigment, degradation products related to LY368842 were identified or tentatively identified using LC/MS/MS. Two degradation products had the same protonated molecular ion at m/z 505, which is 30 amu higher than that of LY368842. The major m/z 505 product has been identified as the indole-2,3-dione oxidative product based on (1)H NMR data and confirmed by an authentic standard. In addition, monohydroxylated product was also identified in the degradation mixture. These degradation products were consistent with the metabolites found in vivo in rats. MALDI-MS analyses of liver and urine pigment both identified a product with a protonated molecular ion at m/z 977, suggesting formation of indirubin-like and indigo-like pigments. The results obtained suggest that the oxidative metabolites of LY368842 played a key role in the formation of the liver and urine pigments.
    Chemical Research in Toxicology 08/2003; 16(7):912-9. DOI:10.1021/tx0201016 · 4.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabolism and pharmacokinetics of moxonidine, a potent central-acting antihypertensive agent, were studied in four healthy subjects after a single oral administration of approximately 1 mg (approximately 60 muCi) of [(14)C(3)]moxonidine. Moxonidine was rapidly absorbed, with peak plasma concentration achieved between 0.5 to 2 h postdose. The maximal plasma concentration and the area under the curve of unchanged moxonidine are lower than those determined for radioactivity, indicating presence of circulating metabolite(s). The total recovery of radiocarbon over 120 h ranged from 99.6 to 105.2%, with 92.3 to 103.3% of the radioactivity excreted in the urine and only 1.9 to 7.3% of the dose excreted in the feces. Thus, renal elimination represented the principal route of excretion of radioactivity. Metabolites of moxonidine were identified in urine and plasma samples by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Oxidation of moxonidine on the methyl group or on the imidazoline ring resulted in the formation of hydroxymethyl moxonidine, hydroxy moxonidine, dihydroxy moxonidine, and dehydrogenated moxonidine. Metabolite profiling results indicated that parent moxonidine was the most abundant component in the urine. The dehydrogenated moxonidine was the major urinary metabolite as well as the major circulating metabolite. Moxonidine also underwent phase II metabolism, generating a cysteine conjugate. In summary, moxonidine is well absorbed after oral administration. The major clearance pathway for moxonidine in humans is via renal elimination. Furthermore, seven metabolites were identified with three metabolites unique to humans.
    Drug Metabolism and Disposition 04/2003; 31(3):334-42. DOI:10.1124/dmd.31.3.334 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabolism and disposition of moxonidine (4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxy-2-methylp yrimidine ), a potent central-acting antihypertensive agent, were investigated in F344 rats. After an i.v. or oral administration of 0.3 mg/kg of [(14)C]moxonidine, the maximum plasma concentrations of moxonidine were determined to be 146.0 and 4.0 ng/ml, respectively, and the elimination half-lives were 0.9 and 1.1 h, respectively. The oral bioavailability of moxonidine was determined to be 5.1%. The metabolic and elimination profiles of moxonidine were determined after an oral administration of 5 mg/kg of [(14)C]moxonidine. More than fifteen phase I and phase II metabolites of moxonidine were identified in the different biological matrices (urine, plasma, and bile). Oxidative metabolism of moxonidine leads to the formation of hydroxymethyl moxonidine and a carboxylic acid metabolite as the major metabolites. Several GSH conjugates, cysteinylglycine conjugates, cysteine conjugates, and a glucuronide conjugate were also identified in rat bile samples. The radiocarbon was eliminated primarily by urinary excretion in rats, with 59.5% of total radioactivity recovered in the urine and 38.4% recovered in the feces within 120 h. In bile duct-cannulated rats, about 39.7% of the radiolabeled dose was excreted in the urine, 32.6% excreted in the bile, and approximately 2% remained in the feces. The results from a quantitative whole body autoradiography study indicate that radiocarbon associated with [(14)C]moxonidine and/or its metabolites was widely distributed to tissues, with the highest levels of radioactivity observed in the kidney and liver. In summary, moxonidine is well absorbed, extensively metabolized, widely distributed into tissues, and rapidly eliminated in rats after oral administration.
    Drug Metabolism and Disposition 05/2000; 28(4):446-59. · 3.33 Impact Factor