scholarly journals Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 220
Author(s):  
Won-Gu Choi ◽  
Ria Park ◽  
Dong Kyun Kim ◽  
Yongho Shin ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Enzyme Activities ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Cytochrome P450s ◽  
Human Liver Microsomes ◽  
Mrna Levels ◽  
Tubulin Inhibitor

Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody–drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug–drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine N-β-d-glucuronidation, with Ki values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25–2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 ± 109.1, 36.8 ± 18.3, 160.6 ± 167.4, 32.1 ± 14.9, 578.4 ± 452.0, 539.5 ± 233.4, 856.7 ± 781.9, and 54.1 ± 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1′-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.

In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

2005 ◽  
Vol 28 (11) ◽  
pp. 1287-1292 ◽  
Author(s):  
Hyojin Kim ◽  
Yune -Jung Yoon ◽  
Hyunmi Kim ◽  
Eun -Young Cha ◽  
Hye Suk Lee ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism

Preclinical Pharmacokinetic and Metabolism of Apixaban, a Potent and Selective Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 910-910 ◽  
Author(s):  
Kan He ◽  
Bing He ◽  
James E. Grace ◽  
Baomin Xin ◽  
Donglu Zhang ◽  
...  
Keyword(s):  
Human Liver ◽  
Small Volume ◽  
Liver Microsomes ◽  
Factor Xa ◽  
Volume Of Distribution ◽  
Human Hepatocytes ◽  
Human Liver Microsomes ◽  
Factor Xa Inhibitor ◽  
Systemic Clearance

Abstract Apixaban is a potent, orally available, highly selective, and reversible factor Xa inhibitor, and currently under development for prevention and treatment of thrombosis. The preclinical pharmacokinetic and metabolism attributes of apixaban feature a small volume of distribution, a low systemic clearance, good oral bioavailability, multiple elimination pathways and minimal potential for drug-drug interactions. Apixaban is well absorbed in chimpanzees, dogs and rats with a mean oral bioavailability of 51, 88 and 34%, respectively. The mean volume of distribution of apixaban is 0.17, 0.29 and 0.31 L/kg in chimpanzees, dogs and rats, respectively, suggesting apixaban is primarily distributed (30–50%) to blood where the therapeutic action resides. The small volume is not due to extensive plasma protein binding, but possibly attributed to limited extravascular tissue distribution, given that the unbound fraction is approximately 13, 5, 8 and 4% in human, chimpanzee, dog and rat serum, respectively. The systemic clearance is <3% of hepatic blood flow in chimpanzees (0.018 L/h/kg) and dogs (0.052 L/h/kg), and <10% in rats (0.26 L/h/kg). Consistent with this low clearance, the in vitro metabolic clearance of apixaban is low, as indicated by the lack of significant metabolism in human liver microsomes and hepatocytes, and in chimpanzee and dog liver microsomes. The primary metabolite identified in vitro is the O-demethylated product which is formed mainly by CYP3A4 in human liver microsomes. The elimination of apixaban involves multiple pathways including renal and intestinal excretion of the parent and metabolism. The biliary clearance is low in dogs, accounting for approximately 2% of the systemic clearance. Apixaban did not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 activities in cDNA-expressed enzyme systems and human liver microsomes, nor induced 1A2, 2B6 and CYP3A4 in human hepatocytes. No glutathione adduct with apixaban was formed in dog and rat, and in human hepatocytes and liver microsomal incubation in the presence of glutathione, suggesting low potential for the formation of reactive metabolites. In conclusion, apixaban shows excellent pharmacokinetic and metabolic properties for clinical development.

scholarly journals Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 776
Author(s):  
Sin-Eun Kim ◽  
Seung-Bae Ji ◽  
Euihyeon Kim ◽  
Minseon Jeong ◽  
Jina Kim ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Human Liver ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Rat Liver Microsomes ◽  
High Resolution Mass ◽  
Resolution Mass

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

P160 - In vitro metabolism of endosulfan sulfate in human liver microsomes, S9 fractions and hepatocytes

2020 ◽  
Vol 35 (1) ◽  
pp. S71-S72
Author(s):  
Hwa-Kyung Lee ◽  
Jeong-Han Kim ◽  
Tae Yeon Kong ◽  
Won-Gu Choi ◽  
Ju-Hyun Kim ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism ◽  
Endosulfan Sulfate
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