Disposition of Taltirelin. (1): Absorption, Distribution, Metabolism and Excretion in Rats and Dogs.

Kodama, Hirohiko; Furuuchi, Satoshi; Takahashi, Masakatsu; Sugihara, Juko; Yoshikawa, Masayoshi

doi:10.2133/dmpk.12.460

Cited by 2 publications

(1 citation statement)

References 15 publications

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“…The differences in the activities of Taltirelin and TRH in the CNS have been attributed to the higher stability of Taltirelin in blood against thyroliberinase, and its higher lipophilicity than TRH that account for its increased penetration across the blood-brain barrier. Taltirelin resistance to hydrolysis by TRH-DE has been questioned, as Taltirelin was rapidly degraded in rat cerebral and pituitary homogenates (Kodama et al, 1997;Kobayashi et al, 2019a), but it is likely that in these homogenates enzymes distinct from TRH-DE were actively degrading Taltirelin.…”

Section: Trh Analogues Resistant To Hydrolysismentioning

confidence: 99%

The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

et al. 2020

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Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH 2) is a peptide mainly produced by brain neurons. In mammals, hypophysiotropic TRH neurons of the paraventricular nucleus of the hypothalamus integrate metabolic information and drive the secretion of thyrotropin from the anterior pituitary, and thus the activity of the thyroid axis. Other hypothalamic or extrahypothalamic TRH neurons have less understood functions although pharmacological studies have shown that TRH has multiple central effects, such as promoting arousal, anorexia and anxiolysis, as well as controlling gastric, cardiac and respiratory autonomic functions. Two G-protein-coupled TRH receptors (TRH-R1 and TRH-R2) transduce TRH effects in some mammals although humans lack TRH-R2. TRH effects are of short duration, in part because the peptide is hydrolyzed in blood and extracellular space by a M1 family metallopeptidase, the TRH-degrading ectoenzyme (TRH-DE), also called pyroglutamyl peptidase II. TRH-DE is enriched in various brain regions but is also expressed in peripheral tissues including the anterior pituitary and the liver, which secretes a soluble form into blood. Among the M1 metallopeptidases, TRH-DE is the only member with a very narrow specificity; its best characterized biological substrate is TRH, making it a target for the specific manipulation of TRH activity. Two other substrates of TRH-DE, Glp-Phe-Pro-NH 2 and Glp-Tyr-Pro-NH 2, are also present in many tissues. Analogs of TRH resistant to hydrolysis by TRH-DE have prolonged central efficiency. Structure-activity studies allowed the identification of residues critical for activity and specificity. Research with specific inhibitors has confirmed that TRH-DE controls TRH actions. TRH-DE expression by b2-tanycytes of the median eminence of the hypothalamus allows the control of TRH flux into the hypothalamus-pituitary portal vessels and may regulate serum thyrotropin secretion. In this review we describe the critical evidences that suggest that modification of TRH-DE activity in tanycytes, and/or in other brain regions, may generate beneficial consequences in some central and metabolic disorders and identify potential drawbacks and missing information needed to test these hypotheses.

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Section: Trh Analogues Resistant To Hydrolysismentioning

confidence: 99%

The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

et al. 2020

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Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats

Kamiya

Otsuka

Miura

et al. 2020

Chem. Res. Toxicol.

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Recently developed high-throughput in vitro assays in combination with computational models could provide alternatives to animal testing. The purpose of the present study was to model the plasma, hepatic, and renal pharmacokinetics of approximately 150 structurally varied types of drugs, food components, and industrial chemicals after virtual external oral dosing in rats and to determine the relationship between the simulated internal concentrations in tissue/plasma and their lowest-observed-effect levels. The model parameters were based on rat plasma data from the literature and empirically determined pharmacokinetics measured after oral administrations to rats carried out to evaluate hepatotoxic or nephrotic potentials. To ensure that the analyzed substances exhibited a broad diversity of chemical structures, their structure-based location in the chemical space underwent projection onto a two-dimensional plane, as reported previously, using generative topographic mapping. A high-throughput in silico one-compartment model and a physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor (gut), metabolizing (liver), central (main), and excreting (kidney) compartments were developed in parallel. For 159 disparate chemicals, the maximum plasma concentrations and the areas under the concentration–time curves obtained by one-compartment models and modified simple PBPK models were closely correlated. However, there were differences between the PBPK modeled and empirically obtained hepatic/renal concentrations and plasma maximal concentrations/areas under the concentration–time curves of the 159 chemicals. For a few compounds, the lowest-observed-effect levels were available for hepatotoxicity and nephrotoxicity in the Hazard Evaluation Support System Integrated Platform in Japan. The areas under the renal or hepatic concentration–time curves estimated using PBPK modeling were inversely associated with these lowest-observed-effect levels. Using PBPK forward dosimetry could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of nephrotoxic or hepatotoxic potential as a part of the risk assessment.

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Disposition of Taltirelin. (1): Absorption, Distribution, Metabolism and Excretion in Rats and Dogs.

Cited by 2 publications

References 15 publications

The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats

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