In vitrometabolism of a novel PPARγagonist, KR-62980, and its stereoisomer, KR-63198, in human liver microsomes and by recombinant cytochrome P450s

Kim, K.-B.; Seo, Kyung-Ah; Yoon, Young-Ran; Bae, Myung Ae; Cheon, Hyae Gyeong; Shin, Jae Gook; Liu, K.-H.

doi:10.1080/00498250802037309

Cited by 11 publications

(8 citation statements)

References 17 publications

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“…Figure 2 shows the inhibitory effects of CYP specific inhibitors on the metabolic clearance rate of glycyrrhetinic acid in HLM. The concentrations of specific inhibitors, furafylline, sulfaphenazole, tranylcypromine, quinidine, diethylthiocarbamate and ketoconazole, were 2, 2, 10, 2, 50 and 2 µ m , respectively, and were chosen based on the published IC50 or K i values for CYP isoforms to ensure adequate inhibitory selectivity and maximal inhibitory potency [13,17–19] . In the presence of 2 µ m of ketoconazole, the metabolic clearance rate of glycyrrhetinic acid decreased to 70% of that of the control (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates

Zhao

Ding

Cao

et al. 2012

Journal of Pharmacy and Pharmacology

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Section: Resultsmentioning

confidence: 99%

In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates

Zhao

Ding

Cao

et al. 2012

Journal of Pharmacy and Pharmacology

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“…In particular, 14-18% of the V max and V max /K m values estimated for CYP3A5 were more than twice those for CYP3A4, and the V max /K m values of vincristine dehydrogenation and KR-63198 hydroxylation by CYP3A5 were more than 10 times those for CYP3A4. 26,38) These results, shown in Fig. 1, strongly suggest the importance of CYP3A5 in metabolism in the human liver and intestine, especially in hydroxylation reactions.…”

Section: Discussionmentioning

confidence: 68%

“…Of interest, the V max /K m values of vincristine dehydrogenation and KR-63198 hydroxylation by CYP3A5 were more than 10 times those for CYP3A4. 26,38) The effects of cytochrome b 5 on the metabolic activities of CYP3A4 and CYP3A5 are summarized in Table 4. 26,32,34,36) For most of the metabolic reactions, the CYP3A5/CYP3A4 ratios of K m , V max , and V max /K m values seem to not be markedly influenced by the addition of cytochrome b 5 .…”

Section: Metabolic Activity Of Cyp3a4 and Cyp3a5mentioning

confidence: 99%

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Niwa

Murayama

Yamazaki

2010

JOURNAL OF HEALTH SCIENCE

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A meta-analysis was performed on the reported literature regarding followings. First, values of the MichaelisMenten constants (K m ), maximal velocities (V max ), and intrinsic clearance (V max /K m ) and the metabolic activities mediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (K i ); and third, maximum inactivation rate constants (k inact ) to establish the contribution of P450 3A5 to drug metabolism. At least 120 of the 127 metabolic reactions investigated (> 94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73 metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of K m , V max , and V max /K m values were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In 14-18% of the metabolic reactions, the V max and V max /K m values for P450 3A5 were more than twice those for P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of 13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P450 3A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

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“…Differences in CYP genes between humans and rats (Nelson et al, 2004) may account for the difference in metabolic stability between the two species. The effect of KR-62980 on the catalytic activities of clinically important human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) is negligible, with IC 50 values > 50 µM KR-62980 for these enzymes (Kim et al, 2008). Therefore, even though KR-62980 may be metabolized rapidly by CYPs in both human and rat livers, no interactions between the elimination of KR-62980 and other drugs are expected.…”

Section: In Vivo Pharmacokinetic Studies Of Kr-62980 In Micementioning

confidence: 96%

“…The metabolic t 1/2 in human liver microsomes (25.8-27.8 min) was approximately twice that in rat liver microsomes (11.5-15.2 min), suggesting greater bioavailability of KR-62980 in humans than in rats. According to a previous study, KR-62980 is metabolized by the liver enzymes CYP1A2, CYP2D6, CYP3A4, and CYP3A5 (Kim et al, 2008). Differences in CYP genes between humans and rats (Nelson et al, 2004) may account for the difference in metabolic stability between the two species.…”

Section: In Vivo Pharmacokinetic Studies Of Kr-62980 In Micementioning

confidence: 98%

Dose-independent pharmacokinetics of a new peroxisome proliferator-activated receptor-γ agonist, KR-62980, in Sprague-Dawley rats and ICR mice

et al. 2011

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The pharmacokinetics of a novel peroxisome proliferator-activated receptor-γ agonist, KR-62980, were characterized in vitro with respect to liver metabolic stability, cell permeability, and plasma protein binding and in vivo using Sprague-Dawley rats and ICR mice. The metabolic half-life of 0.1-10 μM KR-62980 was 11.5-15.2 min in rat liver microsomes and 25.8-28.8 min in human liver microsomes. KR-62980 showed high permeability across MDCK cell monolayers, with apparent permeability coefficients of 20.4 × 10(-6) to 30.8 × 10(-6) cm/sec. The plasma protein binding rate of KR-62980 was 89.4%, and most was bound to serum albumin. After intravenous administration of KR-62980 (2 mg/kg), the systemic clearance was 2.50 L/h/kg, and the volume of distribution at steady-state was 9.16 L/kg. The bioavailability after oral administration was approximately 60.9%. The dose-normalized AUC values were 0.50 ± 0.09, 0.41 ± 0.20, and 0.62 ± 0.08 h · μg/mL after oral administration of 2, 5, and 10 mg/kg KR-62980, respectively, showing no dose-dependency. The in vivo pharmacokinetic parameters in ICR mice were also dose independent. These data suggest that KR-62980 is not significantly dose dependent in rats or mice, although it may disappear rapidly from the systemic circulation via metabolism in the liver.

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In vitrometabolism of a novel PPARγagonist, KR-62980, and its stereoisomer, KR-63198, in human liver microsomes and by recombinant cytochrome P450s

Cited by 11 publications

References 17 publications

In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates

In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Dose-independent pharmacokinetics of a new peroxisome proliferator-activated receptor-γ agonist, KR-62980, in Sprague-Dawley rats and ICR mice

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