Ferrets exhibit similar lung physiology to humans and display similar clinical signs following influenza infection, making them a valuable model for studying high susceptibility and infection patterns. However, the metabolic fate of several common human CYP450 probe substrates in ferrets is still unknown and has not been studied.

OBJECTIVE:

The purpose of this study was to investigate the metabolism of nine human CYP450 probe substrates in ferret hepatocytes and explore their metabolic rate differences between ferrets and other species.

METHOD:

Nine substrates were individually incubated in ferret hepatocytes for up to 120 min. At each time point, 30 μL mixtures were extracted for stability analysis using LC-MS/MS methods. After a 120-minute incubation period, 400 μL of the mixtures were extracted for metabolite identification using UHPLC-QExactive Plus.

RESULTS:

The metabolic clearance was determined as follows: diclofenac > taxol > chlorzoxazone > dextromethorphan > midazolam > omeprazole > bupropion > phenacetin > testosterone. Seven metabolites were identified from phenacetin. Deethylation was found to be the major pathway, and the major metabolite was matched with acetaminophen as probed with the CYP1A2 enzyme. Six metabolites were identified from diclofenac. Glucuronidation was the primary pathway, and a metabolite was found to match 4-OH-diclofenac as probed with the CYP2C9 enzyme. Twenty-two metabolites were identified from omeprazole. The major metabolic pathways included mono-oxygenation and sulfoxide to thioether conversion. No metabolite was found to match with the 5-OH-omeprazole as probed with the CYP2C19 enzyme. Twenty-two metabolites were identified from dextromethorphan. Demethylation was found to be the major metabolic pathway, and one demethylation metabolite was matched with dextrorphan as probed with CYP2D6. Fourteen metabolites were identified from midazolam. Mono-oxygenation was found to be the primary metabolic pathway, and one of the mono-oxygenation metabolites was matched with 1-OH-midazolam as probed with the CYP3A4 enzyme. Eight metabolites were identified from testosterone. Mono-oxygenation and glucuronidation were identified as the major metabolic pathways. One mono-oxygenation was matched with 6-β-testosterone as probed with CYP3A4 enzyme. Six metabolites were identified from taxol. Hydrolysis and mono-oxygenation were the top two metabolic pathways. No metabolite was matched with 6-α-OH-taxol as probed with the CYP2C8 enzyme. Ten metabolites were identified from bupropion. Mono-oxygenation and hydrogenation were identified as the top two metabolic pathways. No mono-oxygenation metabolite was matched with hydroxy-bupropion as probed with the CYP2B6 enzyme. Nine metabolites were identified from chlorzoxazone. Monooxygenation and sulfation were the top two metabolic pathways. One mono-oxygenation metabolite was matched with 6-OH-chlorzoxazone as probed with the CYP2E1 enzyme.

CONCLUSION:

Nine human CYP probe substrates were clearly metabolized in ferret hepatocytes, demonstrating substrate-dependent metabolic rates in ferret hepatocytes and species-dependent metabolic rates in mouse, rat, dog, monkey, and human hepatocytes. Except for 6-a-5-OH-omeprazole, 6-α-OH-taxol, and hydroxy-bupropion, specific metabolites of other six probe substrates in ferret hepatocytes were detected and identified as probed with six human CYP enzymes, respectively.

2000-06-01·Neurotoxicity research3区 · 医学

Neurotrophic factors in neurodegenerative disorders: Model of parkinson’s disease

3区 · 医学

Article

作者: Garcia de Yebenes, J ; Mena, M A ; Yebenes, J

Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis--ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer's disease and peripheral neuropathy--nerve growth factor (NGF) and Parkinson's disease (PD)--glial derived neurotrophic factor (GDNF). In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OH-DA, MPTP, methamphetamine and axotomy. The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic.

1979-05-01·Kidney international1区 · 医学

Feedback regulation of nephron filtration rate during pharmacologic interference with the renin-angiotensin and adrenergic systems in rats

1区 · 医学

Article

作者: Monika Hermle ; Nicholas Stowe ; Jürgen Schnermann

Tubuloglomerular feedback has been defined as a mechanism in which changes in distal tubular sodium chloride delivery induce changes in glomerular arteriolar resistance. Experiments were performed in rats to test the hypothesis that the alterations in vasomotor activity are controlled by local hormonal mechanisms. Early proximal flow rate (EPFR), used as an index of filtration rate, was assessed at loop perfusion rates of 10 and 40 nl/min and during zero loop flow before and during intravenous administration of agents which interfere with the reninangiotensin or adrenergic systems. During infusion of the angiotensin (A) antagonists [Sar1,Ile8-]-AII or [Me2,Gly1,Ile8]-AII at doses ranging from 4.8 to 30.6 micrograms/kg . min, feedback response, expressed as percent change of EPFR during loop flow elevation from 3 to 40 nl/min, fell from a mean of 47.6 +/- 3.3% to 33.2 +/- 2.9% (P less than 0.05). Likewise, after administration of the converting enzyme inhibitor SQ 20881 in a dose ranging between 5.5 and 34.0 mg/kg, feedback response decreased from 48.5 +/- 2.1% to 25.9 +/- 1.9% (P less than 0.001) and returned to 43.1 +/- 5.1% after the inhibitory effect of SQ 20881 on the pressure response to angiotensin I had disappeared. Luminal application of [Sar1,Thr2]-AII (5mM) or of SQ 20881 (5 or 10 mM) had no effect on the feedback response. A significant reduction in the feedback response was noted also during intravenous infusion of propranolol (46.4 +/- 3.2% vs. 29.0 +/- 2.8%, P less than 0.001), whereas 6-OH-dopamine, reserpine, or phenoxybenzamine had no detectable effect. Our results are in agreement with the concept that the renin-angiotensin system may mediate feedback-induced resistance changes. In addition, circulating catecholamines may, in some unknown manner, act as modulators of the feedback response.

100 项与 6-OH-dopa 相关的药物交易

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