T-2307, an arylamidine compound, has been previously reported to have broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens, including Candida species, Cryptococcus neoformans, and Aspergillus species, and is now undergoing clinical trials. Here we investigated the mechanism of action of T-2307 using yeast cells and mitochondria isolated from yeast and rat liver. Nonfermentative growth of Candida albicans and Saccharomyces cerevisiae in glycerol medium, in which yeasts relied on mitochondrial respiratory function, was inhibited at 0.001 to 0.002 g/ml (0.002 to 0.004 M) of T-2307. However, fermentative growth in dextrose medium was not inhibited by T-2307. Microscopic examination using Mitotracker fluorescent dye, a cell-permeant mitochondrion-specific probe, demonstrated that T-2307 impaired the mitochondrial function of C. albicans and S. cerevisiae at concentrations near the MIC in glycerol medium. T-2307 collapsed the mitochondrial membrane potential in mitochondria isolated from S. cerevisiae at 20 M. On the other hand, in isolated rat liver mitochondria, T-2307 did not have any effect on the mitochondrial membrane potential at 10 mM. Moreover, T-2307 had little inhibitory and stimulatory effect on mitochondrial respiration in rat liver mitochondria. In conclusion, T-2307 selectively disrupted yeast mitochondrial function, and it was also demonstrated that the fungal mitochondrion is an attractive antifungal target.
The considerably higher concentrations of T-2307 were selectively accumulated in C. albicans via transporter-mediated systems, as compared with the concentrations in rat hepatocytes. This transporter-mediated uptake of T-2307 contributes to its potent anticandidal activity.
ABSTRACT:We developed 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propionic acid (T-5224) as a novel inhibitor of the c-Fos/activator protein-1 for rheumatoid arthritis therapy. We predicted the metabolism of T-5224 in humans by using human liver microsomes (HLM), human intestinal microsomes (HIM), recombinant human cytochrome P450 (P450), and UDP-glucuronosyltransferases (UGTs). T-5224 was converted to its acyl O-glucuronide (G2) by UGT1A1 and UGT1A3 and to its hydroxyl O-glucuronide (G3) by several UGTs, but it was not metabolized by the P450s. A comparison of the intrinsic clearances (CL int ) between HLM and HIM suggested that the glucuronidation of T-5224 occurs predominantly in the liver. UGT1A1 showed a higher k cat /K m value than UGT1A3 for G2 formation, but a lower k cat /K m value than UGT1A3 for G3 formation. A high correlation was observed between G2 formation activity and UGT1A1-specific activity (-estradiol 3-glucuronidation) in seven individual HLM. A high correlation was also observed between G2 formation activity and UGT1A1 content in the HLM. These results strongly suggest that UGT1A1 is responsible for G2 formation in human liver. In contrast, no such correlation was observed with G3 formation, suggesting that multiple UGT isoforms, including UGT1A1 and UGT1A3, are involved in G3 formation. G2 is also observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite. In this study, we obtained useful information on the metabolism of T-5224 for its clinical use.
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ABSTRACT:Garenoxacin is a novel quinolone that does not have a fluorine substituent at the C-6 position in the quinoline ring. Garenoxacin or 14 C-garenoxacin was intravenously or orally administered to rats, dogs, and monkeys. Metabolic profiles and pharmacokinetic parameters were investigated focusing on the species differences and the allometric scaling of pharmacokinetic parameters. Garenoxacin was well absorbed following oral administration then underwent phase II metabolism in all species tested. Major metabolites of garenoxacin were the sulfate of garenoxacin (M1) and glucuronide (M6). Oxidative metabolites were present in very minor concentrations in all species tested. Another minor route of metabolism was the formation of the carbamoyl glucuronide.Garenoxacin is characterized across species by the observation that it circulates systemically, is excreted renally as unchanged drug, and is metabolized to M1 and M6, which are excreted specifically into the bile. The total clearances (CL) were 12.1, 2.43, and 3.39 ml/min/kg for rats, dogs, and monkeys, respectively. The distribution volume values of garenoxacin (Vss) were 0.88, 1.29, and 0.96 l/kg for rats, dogs, and monkeys, respectively. In all animals tested, the extrarenal clearance was larger than the renal clearance, and neither of the clearances was limited by blood flow. Despite these conditions, garenoxacin showed a good correlation for CL and Vss for allometric interspecies scaling.
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