scholarly journals Content and activity of human liver microsomal protein and prediction of individual hepatic clearance in vivo

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Haifeng Zhang ◽  
Na Gao ◽  
Xin Tian ◽  
Tingting Liu ◽  
Yan Fang ◽  
...  
Keyword(s):  
Human Liver ◽  
Hepatic Clearance ◽  
Microsomal Protein

Characterization of Casearin X Metabolism by Rat and Human Liver Microsomes

Planta Medica ◽  
2018 ◽  
Vol 85 (04) ◽  
pp. 282-291 ◽  
Author(s):  
Rodrigo Moreira da Silva ◽  
Cristiane de Gaitani ◽  
Lucas Marques ◽  
Karina Fraige Baraco ◽  
Alberto Cavalheiro ◽  
...  
Keyword(s):  
Human Liver ◽  
High Performance ◽  
Liver Microsomes ◽  
Hepatic Clearance ◽  
Human Liver Microsomes ◽  
European Medicines Agency ◽  
Antitumor Action ◽  
Pharmacokinetic Data

AbstractCasearin X (CAS X) is the major clerodane diterpene isolated from the leaves of Casearia sylvestris and has been extensively studied due to its powerful cytotoxic activity at low concentrations. Promising results for in vivo antitumor action have also been described when CAS X was administered intraperitoneally in mice. Conversely, loss of activity was observed when orally administered. Since the advancement of natural products as drug candidates requires satisfactory bioavailability for their pharmacological effect, this work aimed to characterize the CAS X metabolism by employing an in vitro microsomal model for the prediction of preclinical pharmacokinetic data. Rat and human liver microsomes were used to assess species differences. A high-performance liquid chromatography with diode-array detection (HPLC-DAD) method for the quantification of CAS X in microsomes was developed and validated according to European Medicines Agency guidelines. CAS X was demonstrated to be a substrate for carboxylesterases via hydrolysis reaction, with a Michaelis-Menten kinetic profile. The enzyme kinetic parameters were determined, and the intrinsic clearance was 1.7-fold higher in humans than in rats. The hepatic clearance was estimated by in vitro-in vivo extrapolation, resulting in more than 90% of the hepatic blood flow for both species. A qualitative study was also carried out for the metabolite identification by mass spectrometry and indicated the formation of the inactive metabolite CAS X dialdehyde. These findings demonstrate that CAS X is susceptible to first-pass metabolism and is a substrate for specific carboxylesterases expressed in liver, which may contribute to a reduction in antitumor activity when administered by the oral route.

Proton MR Spectroscopic Features of the Human Liver: In-Vivo Application to the Normal Condition

1999 ◽  
Vol 40 (1) ◽  
pp. 77
Author(s):  
Soon Gu Cho ◽  
Mi Young Kim ◽  
Young Soo Kim ◽  
Won Choi ◽  
Seok Hwan Shin ◽  
...  
Keyword(s):  
Normal Condition ◽  
Human Liver

Measurements of ultrasonic backscatter coefficients in human liver and kidney in vivo

1995 ◽  
Vol 98 (4) ◽  
pp. 1852-1857 ◽  
Author(s):  
Keith A. Wear ◽  
Brian S. Garra ◽  
Timothy J. Hall
Keyword(s):  
Human Liver ◽  
Liver And Kidney ◽  
Ultrasonic Backscatter

scholarly journals In vitro inhibitory effect of obtusofolin on the activity of CYP3A4, 2C9, and 2E1

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Na Liu ◽  
Ping Chen ◽  
Xiaojun Du ◽  
Junxia Sun ◽  
Shasha Han
Keyword(s):  
Human Liver ◽  
Competitive Inhibition ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Inhibition Model ◽  
Dose Dependent

Abstract Background Obtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin. Methods The effect of obtusofolin on the activity of CYP450s was investigated in the presence of 100 μM obtusofolin in pooled human liver microsomes (HLMs) and fitted with the Lineweaver–Burk plots to characterize the specific inhibition model and kinetic parameters. Results Obtusofolin was found to significantly inhibited the activity of CYP3A4, 2C9, and 2E1. In the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM obtusofolin, the inhibition of these CYP450s showed a dose-dependent manner with the IC50 values of 17.1 ± 0.25, 10.8 ± 0.13, and 15.5 ± 0.16 μM, respectively. The inhibition of CYP3A4 was best fitted with the non-competitive inhibition model with the Ki value of 8.82 μM. While the inhibition of CYP2C9 and 2E1 was competitive with the Ki values of 5.54 and 7.79 μM, respectively. After incubating for 0, 5, 10, 15, and 30 min, the inhibition of CYP3A4 was revealed to be time-dependent with the KI value of 4.87 μM− 1 and the Kinact value of 0.0515 min− 1. Conclusions The in vitro inhibitory effect of obtusofolin implying the potential drug-drug interaction between obtusofolin and corresponding substrates, which needs further in vivo validations.

scholarly journals 2C-B-Fly-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C. elegans: Confirmation with Synthesized Analytical Standards

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 775
Author(s):  
Jitka Nykodemová ◽  
Anna Šuláková ◽  
Petr Palivec ◽  
Hedvika Češková ◽  
Silvie Rimpelová ◽  
...  
Keyword(s):  
Phase I ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Diagnostic Tools ◽  
Cunninghamella Elegans ◽  
Rat Urine ◽  
C Elegans ◽  
Fragmentation Patterns

Compounds from the N-benzylphenethylamine (NBPEA) class of novel psychoactive substances are being increasingly utilized in neurobiological and clinical research, as diagnostic tools, or for recreational purposes. To understand the pharmacology, safety, or potential toxicity of these substances, elucidating their metabolic fate is therefore of the utmost interest. Several studies on NBPEA metabolism have emerged, but scarce information about substances with a tetrahydrobenzodifuran (“Fly”) moiety is available. Here, we investigated the metabolism of 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan-1-amine (2C-B-Fly-NBOMe) in three different systems: isolated human liver microsomes, Cunninghamella elegans mycelium, and in rats in vivo. Phase I and II metabolites of 2C-B-Fly-NBOMe were first detected in an untargeted screening and identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Several hypothesized metabolites were then synthesized as reference standards; knowledge of their fragmentation patterns was utilized for confirmation or tentative identification of isomers. Altogether, thirty-five phase I and nine phase II 2C-B-Fly-NBOMe metabolites were detected. Major detected metabolic pathways were mono- and poly-hydroxylation, O-demethylation, oxidative debromination, and to a lesser extent also N-demethoxybenzylation, followed by glucuronidation and/or N-acetylation. Differences were observed for the three used media. The highest number of metabolites and at highest concentration were found in human liver microsomes. In vivo metabolites detected from rat urine included two poly-hydroxylated metabolites found only in this media. Mycelium matrix contained several dehydrogenated, N-oxygenated, and dibrominated metabolites.

scholarly journals Development and evaluation of a technique for in vivo monitoring of 60Co in human liver

2018 ◽  
Vol 975 ◽  
pp. 012046
Author(s):  
GH Gomes ◽  
MC Silva ◽  
JQ Mello ◽  
ALA Dantas ◽  
BM Dantas
Keyword(s):  
Human Liver ◽  
In Vivo Monitoring
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