Little is known about the kinetics and metabolism of thyroid hormones in the hypothyroid state. To investigate these factors, we developed a reliable method for measurement of serum thyroxine (T 4 ), triiodothyronine (T 3 ), reverse-T 3 (rT 3 ) and stable isotope-labeled T 4 ([ 13 C 9 ]T 4 ), using online solid-phase extraction liquid chromatography-mass spectrometry/mass spectrometry (online SPE LC-MS/MS). We measured supply and turnover rates of T 4 in thyroidectomized (Tx) rats using [ 13 C 9 ]T 4 as a tracer. In rats, serum T 4 , T 3 and rT 3 were decreased but not completely ablated after surgical Tx. Endogenous T 4 and T 3 levels in Tx rats were maintained at a constant low level throughout the experimental period. [ 13 C 9 ]T 4 levels declined with a half-life of w1 . 2 days after it was administered to Tx rats intravenously. These findings strongly suggest that serum T 4 levels in Tx rats are maintained by T 4 supplied by extra-thyroidal tissues (e.g. secretion of extra-thyroidal storage, enhancement of enterohepatic recirculation, and production in extra-thyroidal tissues). Moreover, the turnover rate of T 4 in Tx rats was approximately twofold lower than in controls. This finding suggests that degradation of serum T 4 is repressed by Tx. In conclusion, serum T 4 is maintained at a constant low level by T 4 supply from extra-thyroidal tissues and repression of T 4 degradation in Tx rats. The powerful online SPE LC-MS/MS tool can be used to investigate thyroid hormones kinetics and metabolism, and thus has the potential to be used as a diagnostic tool and to investigate the pathogenesis of thyroid disease.
CYFRA 21-1 is a new tumor marker using two different monoclonal antibodies which recognize the divergent epitope on the N- or C-terminal region of domain 2 of cytokeratin 19 fragment, respectively. In this study, we investigated the relationship between levels of CYFRA 21-1 and survival duration, as well as the efficacy of chemotherapy associated with changes in CYFRA 21-1. Serum samples were obtained from 87 patients with nonoperable lung cancer (35 cases with squamous-cell carcinoma, 33 with adenocarcinoma, 3 with large-cell carcinoma, and 16 with small-cell carcinoma). The cutoff point was set at 3.5 ng/ml. In a CYFRA 21-1 assay, significantly more patients with squamous-cell carcinoma and adenocarcinoma were positive compared to patients with small-cell and large-cell carcinomas (p = 0.0017). Following chemotherapy, blood levels of CYFRA 21-1 decreased significantly in responders versus nonresponders (p = 0.0246). A significant correlation was noted between survival periods and pretreatment levels of CYFRA 21-1 (p = 0.0036). The present study suggests that CYFRA 21-1 might be useful as a possible indicator of survival and therapeutic effect for lung cancer.
We have prepared a series of quinazolinone derivatives linked with piperazinylquinoline for the treatment of irritable bowel syndrome (IBS). Using pharmacophore analysis, we designed and synthesized compounds which bind to both serotonin receptor subtype 1A (5-HT(1A)) and subtype 3 (5-HT(3)). Quinazolinone derivatives with a sulfur atom in the linker showed high affinity in in vitro assays, but low in vivo activity. Focusing on the linker to improve the pharmacokinetic profile, the sulfur atom in the linker was replaced with a methylene group. Further optimization led to the discovery of compound 17m (TZB-30878) ( J. Pharmacol. Exp. Ther. 2007 , 322 , 1315 - 1323 , Patent WO2005082887 (A1), 2005 ), a novel 5-HT(1A) agonist/5-HT(3) antagonist in the 3-aminoquinazolinone series. In in vivo functional assays, 17m dose dependently inhibited the Bezold-Jarisch reflex and induced 5-HT(1A)-mediated behaviors, and in an IBS animal model, 17m significantly inhibited stress-induced defecation. Pretreatment by WAY-100635 (5-HT(1A) antagonist) significantly attenuated but did not abolish the inhibitory effects of 17m. These results suggested that 17m exerted inhibitory effects via both 5-HT(1A) agonistic and 5-HT(3) antagonistic activities and that 17m would be useful as a therapeutic agent for IBS.
5-[(2-Chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001) is a potent p38 mitogen-activated protein kinase inhibitor that is being developed to specifically target the intestines for the treatment of inflammatory bowel disease. According to the ante-drug concept, AKP-001 was designed to be metabolized to inactive forms via the first-pass metabolism to avoid undesirable systemic exposure. The purpose of this study is to investigate the pharmacokinetic characteristics of AKP-001 and its metabolites (M1 and M2) in rats, utilizing a simple physiologically based pharmacokinetic (PBPK) model. In vitro metabolic activity of AKP-001 in the S9 fraction of rat liver was examined, and plasma concentration-time profiles were developed following intravenous and/or oral administration of AKP-001 and its metabolites. AKP-001 was primarily metabolized to M1; however, M2 was not detected in liver S9 fractions. In accordance with this observation in vitro, M2 was detected in plasma after oral dosing of AKP-001 with a lag time of 1.5 hours, but not after intravenous dosing. To analyze pharmacokinetics in rats in vivo, a simple PBPK model was developed by simultaneous fitting of the plasma concentrations after treatment with AKP-001 and its metabolites. The observed plasma concentration-time profiles of AKP-001 and metabolites were described by the model adequately. Intestinal and systemic exposures of AKP-001 were simulated using the model to assess the relationship between pharmacokinetics and efficacy/safety. Model analysis suggested that oral bioavailability of intestinetargeting ante-drugs should be low to avoid systemic side effects. The pharmacokinetic properties of AKP-001 meet this criterion owing to extensive first-pass metabolism.
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