Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css-MRTpo method and chimeric mice with humanised livers
Xenobiotica. 2023 Nov 8:1-26. doi: 10.1080/00498254.2023.2280785. Online ahead of print.ABSTRACTPredicting plasma concentration-time profiles of disproportionate metabolites in humans is crucial for evaluating metabolites according to the Safety Testing guidelines. We evaluated Css-MRTpo, an empirical method, using chimeric mice with humanised livers capable of generating human-disproportionate metabolites.Azilsartan and AZ-M2 were administered to humanised chimeric mice, and pharmacokinetic parameters were obtained. Pharmacokinetic data for DS-1971a and DS-M1 in humanised chimeric mice were obtained from the literature. T...
Source: Xenobiotica - November 8, 2023 Category: Research Authors: Hidetaka Kamimura Shotaro Uehara Nao Yoneda Hiroshi Suemizu Source Type: research
Tree shrew cytochrome P450 2E1 is a functional enzyme that metabolises chlorzoxazone and < em > p < /em > -nitrophenol
In this study, a novel CYP2E1 was isolated from tree shrew liver and was characterised in comparison with human, dog, and pig CYP2E1. Tree shrew CYP2E1 and human CYP2E1 showed high amino acid sequence identity (83%) and were closely related in a phylogenetic tree.Gene and genome structures of CYP2E1 were generally similar in humans, dogs, pigs, and tree shrews. Tissue expression patterns showed that tree shrew CYP2E1 mRNA was predominantly expressed in liver, just as for dog and pig CYP2E1 mRNAs. In tree shrews, recombinant CYP2E1 protein and liver microsomes metabolised chlorzoxazone and p-nitrophenol, probe substrates of...
Source: Xenobiotica - November 7, 2023 Category: Research Authors: Genki Ushirozako Norie Murayama Kyoko Tsukiyama-Kohara Hiroshi Yamazaki Yasuhiro Uno Source Type: research
Tree shrew cytochrome P450 2E1 is a functional enzyme that metabolises chlorzoxazone and < em > p < /em > -nitrophenol
In this study, a novel CYP2E1 was isolated from tree shrew liver and was characterised in comparison with human, dog, and pig CYP2E1. Tree shrew CYP2E1 and human CYP2E1 showed high amino acid sequence identity (83%) and were closely related in a phylogenetic tree.Gene and genome structures of CYP2E1 were generally similar in humans, dogs, pigs, and tree shrews. Tissue expression patterns showed that tree shrew CYP2E1 mRNA was predominantly expressed in liver, just as for dog and pig CYP2E1 mRNAs. In tree shrews, recombinant CYP2E1 protein and liver microsomes metabolised chlorzoxazone and p-nitrophenol, probe substrates of...
Source: Xenobiotica - November 7, 2023 Category: Research Authors: Genki Ushirozako Norie Murayama Kyoko Tsukiyama-Kohara Hiroshi Yamazaki Yasuhiro Uno Source Type: research
< em > N, N < /em > -dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an < em > in vitro < /em > investigation
Xenobiotica. 2023 Nov 2:1-8. doi: 10.1080/00498254.2023.2278488. Online ahead of print.ABSTRACTN, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT.This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high-...
Source: Xenobiotica - November 2, 2023 Category: Research Authors: Emma Eckern äs Alicia Macan-Sch önleben Moa Andresen-Bergstr öm Sofia Birgersson Kurt-J ürgen Hoffmann Michael Ashton Source Type: research
< em > N, N < /em > -dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an < em > in vitro < /em > investigation
Xenobiotica. 2023 Nov 2:1-10. doi: 10.1080/00498254.2023.2278488. Online ahead of print.ABSTRACTN, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT.This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high...
Source: Xenobiotica - November 2, 2023 Category: Research Authors: Emma Eckern äs Alicia Macan-Sch önleben Moa Andresen-Bergstr öm Sofia Birgersson Kurt-J ürgen Hoffmann Michael Ashton Source Type: research
< em > N, N < /em > -dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an < em > in vitro < /em > investigation
Xenobiotica. 2023 Nov 2:1-10. doi: 10.1080/00498254.2023.2278488. Online ahead of print.ABSTRACTN, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT.This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high...
Source: Xenobiotica - November 2, 2023 Category: Research Authors: Emma Eckern äs Alicia Macan-Sch önleben Moa Andresen-Bergstr öm Sofia Birgersson Kurt-J ürgen Hoffmann Michael Ashton Source Type: research
< em > N, N < /em > -dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an < em > in vitro < /em > investigation
Xenobiotica. 2023 Nov 2:1-10. doi: 10.1080/00498254.2023.2278488. Online ahead of print.ABSTRACTN, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT.This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high...
Source: Xenobiotica - November 2, 2023 Category: Research Authors: Emma Eckern äs Alicia Macan-Sch önleben Moa Andresen-Bergstr öm Sofia Birgersson Kurt-J ürgen Hoffmann Michael Ashton Source Type: research
Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1
This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 subst...
Source: Xenobiotica - October 27, 2023 Category: Research Authors: Wenjing Yuan Shanshan Kou Ying Ma Yusi Qian Xinyu Li Yuanyuan Chai Zhenzhou Jiang Luyong Zhang Lixin Sun Xin Huang Source Type: research
Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1
This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 subst...
Source: Xenobiotica - October 27, 2023 Category: Research Authors: Wenjing Yuan Shanshan Kou Ying Ma Yusi Qian Xinyu Li Yuanyuan Chai Zhenzhou Jiang Luyong Zhang Lixin Sun Xin Huang Source Type: research
Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1
This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 subst...
Source: Xenobiotica - October 27, 2023 Category: Research Authors: Wenjing Yuan Shanshan Kou Ying Ma Yusi Qian Xinyu Li Yuanyuan Chai Zhenzhou Jiang Luyong Zhang Lixin Sun Xin Huang Source Type: research
Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1
This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 subst...
Source: Xenobiotica - October 27, 2023 Category: Research Authors: Wenjing Yuan Shanshan Kou Ying Ma Yusi Qian Xinyu Li Yuanyuan Chai Zhenzhou Jiang Luyong Zhang Lixin Sun Xin Huang Source Type: research
Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1
This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 subst...
Source: Xenobiotica - October 27, 2023 Category: Research Authors: Wenjing Yuan Shanshan Kou Ying Ma Yusi Qian Xinyu Li Yuanyuan Chai Zhenzhou Jiang Luyong Zhang Lixin Sun Xin Huang Source Type: research
Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1
This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 subst...
Source: Xenobiotica - October 27, 2023 Category: Research Authors: Wenjing Yuan Shanshan Kou Ying Ma Yusi Qian Xinyu Li Yuanyuan Chai Zhenzhou Jiang Luyong Zhang Lixin Sun Xin Huang Source Type: research
Evobrutinib pathway to its major metabolite M463-2 and insights from a biotransformation and DDI perspective
Xenobiotica. 2023 Oct 25:1-12. doi: 10.1080/00498254.2023.2272180. Online ahead of print.ABSTRACT1. Evobrutinib is a highly selective, covalent, central nervous system-penetrant Bruton's tyrosine kinase (BTK) inhibitor, currently in Phase III trials for the treatment of relapsing multiple sclerosis. One major circulating metabolite of evobrutinib has been previously identified as the racemic dihydro-diol M463-2 (MSC2430422) in a Phase I human mass balance study.2. Phenotyping experiments were conducted to confirm the metabolic pathway of evobrutinib to M463-2. Ratio of the enantiomers was determined by enantioselective liq...
Source: Xenobiotica - October 26, 2023 Category: Research Authors: Holger Scheible Hanno Schieferstein Ralf Schmidt Klaus Pusecker Ulrike Gradhand Sathej Gopalakrishnan Khalid Iqbal Jennifer Dong Reinaldo Jones Claudia Meli Jayaprakasam Bolleddula Martin Dyroff Katrin Georgi Source Type: research
Evobrutinib pathway to its major metabolite M463-2 and insights from a biotransformation and DDI perspective
Xenobiotica. 2023 Oct 25:1-12. doi: 10.1080/00498254.2023.2272180. Online ahead of print.ABSTRACT1. Evobrutinib is a highly selective, covalent, central nervous system-penetrant Bruton's tyrosine kinase (BTK) inhibitor, currently in Phase III trials for the treatment of relapsing multiple sclerosis. One major circulating metabolite of evobrutinib has been previously identified as the racemic dihydro-diol M463-2 (MSC2430422) in a Phase I human mass balance study.2. Phenotyping experiments were conducted to confirm the metabolic pathway of evobrutinib to M463-2. Ratio of the enantiomers was determined by enantioselective liq...
Source: Xenobiotica - October 26, 2023 Category: Research Authors: Holger Scheible Hanno Schieferstein Ralf Schmidt Klaus Pusecker Ulrike Gradhand Sathej Gopalakrishnan Khalid Iqbal Jennifer Dong Reinaldo Jones Claudia Meli Jayaprakasam Bolleddula Martin Dyroff Katrin Georgi Source Type: research
