Circulating metabolites

It is clear however) that 25-OH-D3 is the major circulating metabolite of vitamin D3. It circulates almost completely bound to a specific serum globulin. 

The M20 metabolite is a major circulating metabolite of dasatinib (SPRY CEL) in humans [77]. A large quantity of M20 was needed to serve as an analytical standard, but was not readily accessible by mammalian bioreactors or chemical synthesis. Microbial biotransformation was used to make the metabolite to support the development of dasatinib [58]. 

The short plasma half-life of dobutamine (1-2 minutes) was found by Murphy et al. (4) to be due to the rapid redistribution of the drug from the plasma to the tissue. However, plasma half-life of radioactivity following the administration of 14C-dobutamine was 1.9 hours. The major circulating metabolite is the glucuronide conjugate of 3-0-methyldobutamine. During a continuous intravenous infusion of dobutamine, the plasma level of the parent drug reach a maximum within 8 to 10 minutes, while those of the metabolites peak be-... 

The elimination half-life of the main circulating metabolite was 8 hours with approximately 50% excreted in the urine and approximately 46% in the feces 5 days after dosing. 

Limonene was extensively metabolized by a variety of mammalian species [279, 290, 292, 301]. Its principal circulating metabolites identified in the rat were perillic acid and dihydroperillic acid. These components were effective inhibitors of isoprenylation and cellular proliferation in vitro [271]. 

Certain human populations depend on dietary sources of vitamin D because of insufficient biosynthesis of the vitamin due to inadequate skin exposure to sunlight. The classic symptoms of vitamin D deficiency are rickets in children and osteomalacia in adults. 25-Hydroxyvitamin D3 is the major circulating metabolite in the blood, but the hormonally active form of the vitamin is 1,25-dihydroxyvitamin D3. The latter metabolite stimulates the intestine to absorb calcium and phosphate by two independent mechanisms and acts with parathyroid hormone to mobilize calcium, accompanied by phosphate, from the bone fluid compartment into the bloodstream. 1,25-dihydroxyvitamin D 3 is also involved in the formation of osteoclasts—giant cells that are solely responsible for the resorption of bone matrix (33). Resorption is an essential process for the development, growth, maintenance, and repair of bone. 

All these studies suggest that the metabolic pathway is the same for free and bound forms of ferulic acid. Whereas the free form is rapidly absorbed, metabolized and excreted in urine, the bound form allows a longer time period (free and conjugated) in plasma, as already suggested by the absence of free ferulic acid in rat plasma 18 h after intake from an enriched diet, whereas its metabolites were still present [Adam et al., 2002]. Even though its bioavailability, in terms of half-life in plasma and low excretion in urine, was improved when esterified, the absorption of ferulic acid from a wheat source was lower than if present as free form in a diet [Rondini et al., 2004]. This indicates that the amounts of ferulic acid circulating in plasma as well as its circulating metabolites are dependent on its form present in the food source. 

To fully understand the actual mechanism of action of dietary flavonoids either as antioxidants, modulators of cell signalling, or inflammatory pathways, it is important to detect and identify their metabolites in vivo as well as to study the consequences of interaction of these circulating metabolites with cells. Animal models and human studies should also be conducted to identify the in vivo mechanism of action of dietary flavonoids. Results of such studies are crucial in the evaluation of their potential as cardiovascular protective agents and may eventually lead to specific advice regarding intake of foods and beverages rich in flavonoids and attempts to alter and enhance flavonoid content of a range of foods. 

Perform radiolabeled human ADME study as early as possible to define a major circulating metabolite. 

A major circulating metabolite is defined to be a drug derived component(s) accounting for 25% or more of the AUC of total circulating drug derived components (relative abundance). 

Any major human circulating metabolites should be considered for monitoring in toxicological and/or clinical studies. 

If a unique or human specific circulating metabolite is absent or present at relatively low concentration in toxicological species, separate studies to evaluate the toxicity of the human specific metabolite are warranted. 

All human circulating metabolites that account for >10% of the administered dose or systemic exposure (whichever is less) and that were not present at sufficient levels to permit adequate evaluation during nonclinical animal studies should be considered for additional safety/ toxicological testings. 

If the systemic exposure for a major human circulating metabolite is equivalent to that observed in nonclinical toxicological species, then the metabolite levels may be sufficient to limit additional toxicity testing using the major human metabolite. 

Focus changed from metabolites accounting for >10% of the administered dose (which could potentially apply to circulating as well as metabolites in excreta) to circulating metabolites accounting for >10% of parent drug s systemic exposure. 

Seto, C., Ni, J., Ouyang, F., Ellis, R., Aiello, M., Jones, E. B., Welty, D., and Acheampong, A. (2007). Detection of circulating metabolites of carbamazepine in microdosing studies in rats using LC-MS/MS. In Proceedings of the 55th ASMS Conference on Mass Spectrometry and Allied Topics. ASMS, Indianapolis, IN. 

High-sensitivity techniques for the quantitation and characterization of circulating metabolites following administration of radiolabeled compounds are of critical importance to understand the safety and efficacy profiles of novel drug candidates. AMS is one of the most sensitive techniques for the detection of radiolabeled components. However, the high cost and slow throughput of AMS analysis preclude the routine use of the techniques for metabolism studies. 

If one or more major circulating metabolites contribute significantly to the pharmacological action of a drug or if there are safety issues associated with such metabolites, reaction phenotyping for the individual metabolites should be considered. 

Progestogens do not undergo enterohepatic circulation. Metabolites are excreted in the faeces and urine. Only a small proportion of a dose of progestogen is excreted unchanged in the urine. 

Disposition in the Body. Readily absorbed after oral administration. It is metabolised by reduction to the sulphide which is active and is the predominant circulating metabolite, reaching a concentration about 25% of that of sulphinpyrazone. It is also oxidised to the sulphone (active) and there are several hydroxy metabolites. All metabolites are excreted in the urine as the C-glucuronides, only a small proportion being excreted in... 

B), the hydroxylamine metabolite (Scheme 10, C), the nitrones (D and E), the lactam metabolite (Scheme 10, F), the hydroxylated 0-dealkylated metabolite (G), the glucuronide of metabolite G (Scheme 10, H), the oxime metabolite (Scheme 10,1), and the keto acid metabolite (Scheme 10, J)—were characterized by high-resolution LC/MS and LC/MS/MS (Table 7-10). The authors found that the major circulating metabolite observed in vivo was generated... 

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