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Identification of [14C]fluasterone metabolites in urine and feces collected from dogs after subcutaneous and oral administration of [14C]fluasterone.

ABSTRACT: The objective of this research was the identification of the metabolic profile of fluasterone, a synthetic derivative of dehydroepiandrosterone, in dogs treated orally or subcutaneously with [4-(14)C]fluasterone. Separation and characterization techniques used to identify the principal metabolites of fluasterone in urine and feces included high-performance liquid chromatography (HPLC), liquid scintillation spectrometry, HPLC/tandem mass spectrometry, and NMR. In urine, the majority of the radioactivity was present as two components that had apparent molecular weights consistent with their tentative identification as monoglucuronide conjugates of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol and X(alpha or beta)-4alpha-dihydroxy-16alpha-fluoro-5-androsten-17beta-ol. The identification of the monoglucuronide conjugate of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol was also supported by NMR data. In support of this identification, these metabolites were cleaved with glucuronidase enzyme treatment, which gave rise to components with molecular weights again consistent with the aglycones of a monohydroxylated, 17-keto reduced (dihydroxy) fluasterone metabolite and a dihydroxylated, 17-keto reduced (trihydroxy) fluasterone metabolite. In feces, nonconjugated material predominated. The primary metabolites eliminated in feces were the two hydroxy fluasterone metabolites arising from 17-reduction (16alpha-fluoro-5-androsten-17beta-ol and 16alpha-fluoro-5-androsten-17alpha-ol) and 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol that was present in urine in glucuronide form.

SUBMITTER: Burgess JP

PROVIDER: S-EPMC2683393 | biostudies-other | 2009 May

REPOSITORIES: biostudies-other

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Project description:BackgroundWe previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model.Methodology/principal findingsMPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed.ConclusionsPPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.

Project description:Obesity is a complex multifactorial phenotype that influences several metabolic pathways. Yet, few studies have examined the relations of different body fat compartments to urinary and serum metabolites. Anthropometric phenotypes (visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), the ratio between VAT and SAT (VSR), body mass index (BMI), waist circumference (WC)) and urinary and serum metabolite concentrations measured by nuclear magnetic resonance spectroscopy were measured in a population-based sample of 228 healthy adults. Multivariable linear and logistic regression models, corrected for multiple testing using the false discovery rate, were used to associate anthropometric phenotypes with metabolites. We adjusted for potential confounding variables: age, sex, smoking, physical activity, menopausal status, estimated glomerular filtration rate (eGFR), urinary glucose, and fasting status. In a fully adjusted logistic regression model dichotomized for the absence or presence of quantifiable metabolite amounts, VAT, BMI and WC were inversely related to urinary choline (ß = -0.18, p = 2.73*10-3), glycolic acid (ß = -0.20, 0.02), and guanidinoacetic acid (ß = -0.12, p = 0.04), and positively related to ethanolamine (ß = 0.18, p = 0.02) and dimethylamine (ß = 0.32, p = 0.02). BMI and WC were additionally inversely related to urinary glutamine and lactic acid. Moreover, WC was inversely associated with the detection of serine. VAT, but none of the other anthropometric parameters, was related to serum essential amino acids, such as valine, isoleucine, and phenylalanine among men. Compared to other adiposity measures, VAT demonstrated the strongest and most significant relations to urinary and serum metabolites. The distinct relations of VAT, SAT, VSR, BMI, and WC to metabolites emphasize the importance of accurately differentiating between body fat compartments when evaluating the potential role of metabolic regulation in the development of obesity-related diseases, such as insulin resistance, type 2 diabetes, and cardiovascular disease.

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Identification of [14C]fluasterone metabolites in urine and feces collected from dogs after subcutaneous and oral administration of [14C]fluasterone.

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