Background: PPAR␥ ligands can be used in numerous metabolic syndromes. Results: A novel non-agonist PPAR␥ ligand, UHC1 exhibited great beneficial effects on glucose metabolism and anti-inflammatory response. Conclusion: UHC1 shows anti-diabetic action by blocking CDK5-mediated PPAR␥ phosphorylation. Significance: UHC1 can be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.
ABSTRACT:Midazolam undergoes oxidative hydroxylation by CYP3A to its metabolites, which are excreted mainly as glucuronidated conjugates into the urine. In this study, we examined the glucuronidation of hydroxymidazolam in human liver microsomes (HLMs) and characterized the UDP-glucuronosyltransferases (UGTs) involved in 1-and 4-hydroxymidazolam glucuronidation.Among the 12 UGT isoforms tested, the O-and N-glucuronidation of 1-hydroxymidazolam was mediated by UGT2B4/2B7 and 1A4, respectively. In contrast, the glucuronidation of 4-hydroxymidazolam was mediated by UGT1A4. Consistent with these observations, the UGT1A4 inhibitor hecogenin and the UGT2B7 substrate diclofenac potently inhibited the N-and Oglucuronidation of 1-hydroxymidazolam in HLMs, respectively. A correlation analysis of UGT enzymatic activity and the formation rate of glucuronide metabolites from 1-and 4-hydroxymidazolam in 25 HLMs showed that hydroxymidazolam glucuronidation is correlated with UGT1A4-mediated lamotrigine glucuronidation and UGT2B7-mediated diclofenac glucuronidation activity. Taken together, these findings indicate that UGT1A4, 2B4, and 2B7 are major isoforms responsible for glucuronide conjugate formation from 1-and 4-hydroxymidazolam, which are the two major oxidative metabolites of midazolam.
ABSTRACT:The role of the genetically polymorphic CYP3A5 in the metabolism of CYP3A substrates is unclear. We investigated the contributions of the CYP3A4 and CYP3A5 isoforms to the metabolism of the phosphodiesterase type 5 inhibitors (PDE5Is) sildenafil, udenafil, and vardenafil. In vitro incubation studies of sildenafil N-demethylation, udenafil N-dealkylation, and vardenafil N-deethylation were conducted using recombinant CYP3A enzymes and 15 human liver microsome (HLM) preparations with predetermined CYP3A5 genotypes. Recombinant CYP3A4 and CYP3A5 both produced N-desalkyl metabolites of sildenafil, udenafil, and vardenafil. The catalytic efficiency (Cl int ؍ V max /apparent K m ) of the rCYP3A5 isoform for vardenafil N-deethylation was about 3.2-fold that of rCYP3A4, whereas the intrinsic clearance rates for N-dealkylation of both sildenafil and udenafil were similar between rCYP3A5 and rCYP3A4. The metabolite formation activity was higher in HLMs heterozygous for the CYP3A5*3 allele (n ؍ 9) than in HLMs homozygous for CYP3A5*3 (n ؍ 6). These findings suggest that CYP3A5 and CYP3A4 play a significant role in the metabolism of PDE5Is. The genetic polymorphism of CYP3A5 may contribute to interindividual variability in the disposition of PDE5Is, especially vardenafil. Further in vivo studies are needed to confirm the effects of CYP3A5 genotypes on the pharmacokinetics of PDE5Is.Sildenafil, udenafil, and vardenafil are potent, selective inhibitors of cyclic GMP-specific phosphodiesterase type 5 (PDE5) in the smooth muscle cells lining blood vessels, especially in the corpus cavernosum of the penis. These drugs are used for effective p.o. treatment of erectile dysfunction. Previous studies have reported large interindividual variability in the pharmacokinetic disposition of sildenafil, udenafil, and vardenafil (Klotz et al., 2001;Rajagopalan et al., 2003;Shim et al., 2003;Bischoff, 2004;Gupta et al., 2005;Mehrotra et al., 2007). Vardenafil showed the highest interindividual variation among three PDE5 inhibitors (PDE5Is), with a 14-fold variability among subjects receiving 20 mg of vardenafil (Klotz et al., 2001;Rajagopalan et al., 2003). The mechanisms of these large interindividual variations in vivo have not been elucidated.Sildenafil, udenafil, and vardenafil undergo N-dealkylation in the liver and intestine, and cytochrome P450 (P450) 3A is primarily involved in their metabolism (Fig. 1) (Ji et al., 2004; Kivisto et al., 2004;Mehrotra et al., 2007). CYP3A is most abundant human hepatic P450 and is involved in the metabolism of approximately 50% of commonly administered drugs (Evans and Relling, 1999). In adults, CYP3A4 and CYP3A5 are predominant among the four known isoforms (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) in the liver and intestine (Nelson et al., 1996). CYP3A5 is similar to CYP3A4 with regard to sequence and substrate selectivity (Kuehl et al., 2001). There are 84% amino acid sequence similarity and overlapping substrate specificities between CYP3A4 and CYP3A5 (Aoyama et al., 1989;Wrighton and ...
Transition-metal oxides such as WO 3 are of interest because of their photochromic, electrochromic, and photocatatytic properties, which are promising for a variety of applications in mirrors, windows, and gas sensor technologies. These applications require a detailed understanding of the morphology, particle size, and other material characteristics for effective utilization and implementation. We present a correlation between powder particle size, determined from dynamic light scattering, and the bonding characteristics of WO 3 powders, showing that the W−O−W/WO integrated intensity ratio is directly related to the particle size of our powders and not just to the grain size of WO 3 films, as has previously been shown. This correlation can serve as a complementary technique to gauge particle size as well as crystallinity in WO 3 powders. When the WO signal is high and the W−O−W is low, the powders will be of small particle size and/or of lower crystallinity. Thus, this analysis provides a useful approach for obtaining powder particle size in WO 3 powders. The analysis might also prove useful for powders that exhibit Raman behavior similar to that of WO 3 .
We identified cytochrome P450 (P450) isozymes that are involved in the formation of two active sibutramine (N-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites, M1 (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine) and M2 (1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine), in humans using a combination chemical inhibition, correlation analyses in human liver microsomes (HLMs), and activity assays using recombinant P450s. Mechanism-based CYP2B6 inhibitors (i.e., clopidogrel, ticlopidine, and triethylenethiophoramide) significantly inhibited the formation of M1 from sibutramine and M2 from M1, respectively; in contrast, no effect was observed when using potent inhibitors of eight P450 isozymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A). In addition, the formations of M1 from sibutramine (r ؍ 0.694, p ؍ 0.0029) and M2 from M1 (r ؍ 0.834, p < 0.0001) were strongly correlated with CYP2B6-catalyzed bupropion hydroxylation in 16 different HLM panels. Furthermore, recombinant CYP2B6 catalyzed M1 and/or M2 formation at the highest rate among 10 P450s. Although recombinant CYP2C19, 3A4, and 3A5 also catalyzed, to a less extent, M1 formation at high substrate concentrations (>5 M), those contributions might be minor considering usual concentrations of sibutramine and M1 in the clinical setting. The kinetics of M1 and/or M2 formation from sibutramine in HLMs were fitted by a two-enzyme model, and the mean apparent K m value (4.79 M) for high-affinity component was similar to that observed in recombinant CYP2B6 (8.02 M). In conclusion, CYP2B6 is the primary catalyst for the formation of sibutramine two active metabolites, which may suggest that pharmacogenetics and drug interactions of sibutramine in relation to CYP2B6 activity should be considered in the pharmacotherapy of sibutramine.Sibutramine (Fig. 1) hydrochloride monohydrate is one of the few established treatment for obesity (Arterburn et al., 2004; IoannidesDemos et al., 2006). As a central serotonergic and noradrenergic reuptake inhibitor, sibutramine activates a combination of serotoninand noradrenaline-mediated mechanisms to increase satiety and energy expenditure and decrease body weight (Heal et al., 1998;Luque and Rey, 1999).In humans, sibutramine is rapidly absorbed from the gastrointestinal tract after oral administration, with an average bioavailability of 77% (Lean, 1997;Luque and Rey, 1999). After absorption, sibutramine undergoes extensive hepatic metabolism, rapidly N-demethylated to form the pharmacologically active metabolites, M1 (Fig. 1) and then subsequently demethylated into M2 (Fig. 1). M1 and M2 further undergo hydroxylation and glucuronide conjugation to form inactive metabolites (M5 and M6), which are mainly excreted in urine (Stock, 1997;Hind et al., 1999;Chen et al., 2003;Link et al., 2006). The pharmacological effects of sibutramine are mostly attributable to the M1 and M2, which inhibit monoamine reuptake in vitro more effectively than sibutramine i...
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