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

Choi, Won-Gu; Park, Ria; Kim, Dong Kyun; Shin, Yongho; Cho, Yong‐Yeon; Lee, Hye Suk

doi:10.3390/pharmaceutics12030220

Cited by 3 publications

(2 citation statements)

References 42 publications

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“…Hepatic microsomes and cell models were evaluated for drug–drug interactions by assessing activity and mRNA expression levels of metabolic enzymes or transporters. Currently, common liver microsomes include rat, mouse, and human liver microsomes (RLMs, MLMs, and HLMs), and hepatocytes commonly include mouse, rat, monkey, and human hepatocytes [ 30 , 31 , 32 ]. For application, this model can be utilized to evaluate the DDI caused by TDI and reverse inhibition of enzymes [ 33 ].…”

Section: Pharmacokinetic Interactionsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Drug–Drug Interactions: Research Methods and Applications

Sun,

Mi,

Hou

et al. 2023

Metabolites

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Because of the high research and development cost of new drugs, the long development process of new drugs, and the high failure rate at later stages, combining past drugs has gradually become a more economical and attractive alternative. However, the ensuing problem of drug–drug interactions (DDIs) urgently need to be solved, and combination has attracted a lot of attention from pharmaceutical researchers. At present, DDI is often evaluated and investigated from two perspectives: pharmacodynamics and pharmacokinetics. However, in some special cases, DDI cannot be accurately evaluated from a single perspective. Therefore, this review describes and compares the current DDI evaluation methods based on two aspects: pharmacokinetic interaction and pharmacodynamic interaction. The methods summarized in this paper mainly include probe drug cocktail methods, liver microsome and hepatocyte models, static models, physiologically based pharmacokinetic models, machine learning models, in vivo comparative efficacy studies, and in vitro static and dynamic tests. This review aims to serve as a useful guide for interested researchers to promote more scientific accuracy and clinical practical use of DDI studies.

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Section: Pharmacokinetic Interactionsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Drug–Drug Interactions: Research Methods and Applications

Sun,

Mi,

Hou

et al. 2023

Metabolites

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“…The success of a SMDC is greatly reliant on the choice of cytotoxic agent. Mertansine, also known as DM1, is a highly cytotoxic member of the maytansinoid family [ 27 ]. DM1 is a microtubule-disrupting agent; it binds to tubulin in order to block the microtubule assembly.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of ePSMA-DM1: A New Theranostic Small-Molecule Drug Conjugate (T-SMDC) for Prostate Cancer

et al. 2023

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Small-molecule drug conjugates (SMDCs) are compounds in which a therapeutic payload is conjugated to a targeting vector, for specific delivery to the tumor site. This promising approach can be translated to the treatment of prostate cancer by selecting a targeting vector which binds to the prostate-specific membrane antigen (PSMA). Moreover, the addition of a bifunctional chelator to the molecule allows for the use of both diagnostic and therapeutic radionuclides. In this way, the distribution of the SMDC in the body can be monitored, and combination therapy regimes can be implemented. We combined a glutamate-urea-lysine vector to the cytotoxic agent DM1 and a DOTA chelator via an optimized linker to obtain the theranostic SMDC (T-SMDC) ePSMA-DM1. ePSMA-DM1 retained a high binding affinity to PSMA and demonstrated PSMA-specific uptake in cells. Glutathione stability assays showed that the half-life of the T-SMDC in a reducing environment was 2 h, and full drug release was obtained after 6 h. Moreover, 100 nM of ePSMA-DM1 reduced the cell viability of the human PSMA-positive LS174T cells by >85% after 72 h of incubation, which was comparable to a 10-fold higher dose of free DM1. [111In]In-ePSMA-DM1 and [177Lu]Lu-ePSMA-DM1 were both obtained in high radiochemical yields and purities (>95%), with >90% stability in PBS and >80% stability in mouse serum for up to 24 h post incubation at 37 °C. SPECT/CT imaging studies allowed for a faint tumor visualization of [111In]In-ePSMA-DM1 at 1 h p.i., and the ex vivo biodistribution showed tumor uptake (2.39 ± 0.29% ID/g) at 1 h p.i., with the compound retained in the tumor for up to 24 h. Therefore, ePSMA-DM1 is a promising T-SMDC candidate for prostate cancer, and the data obtained so far warrant further investigations, such as therapeutic experiments, after further optimization.

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Pharmacokinetic Drug-Drug Interactions: A Systematic Review of the Cytochrome P450 (CYP) Isoenzyme 3A4

Ainurofiq,

Ismaya

2023

RJPT

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The cytochrome P450 (CYP) isoenzyme 3A4 or CYP3A4 is a major drug-metabolizing enzyme that has the potential to cause pharmacokinetic drug-drug interactions. Primary research studies have demonstrated CYP3A4-mediated drug-drug interactions through a variety of mechanisms. However, there has been no review during the last 10 years of pharmacokinetic drug-drug interactions mediated by CYP3A4 isoenzymes. It is necessary to systematically review the pharmacokinetic drug-drug interactions mediated by CYP3A4. Source review of articles were retrieved from the PubMed and Scopus databases. The preparation of keywords through the population, intervention, comparison, and outcomes (PICO) method written based on the Boolean operator. Reporting the results of the paper search is presented in the Prisma version 1 2020 flowchart. The risk of bias assessment used COHORT tools and Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tools. Data was analyzed narratively. Pharmacokinetic drug interactions are mediated by CYP3A4 through the mechanism of induction, activation, inhibition, and inactivation. Induction or activation of CYP3A4 can cause an increase in CYP3A4 expression, so that the drug is metabolized more quickly and has the potential to lose drug efficacy. Inhibition and inactivation of CYP3A4 causes plasma drug levels to increase and drug elimination time to last longer. CYP3A4 plays a major role in the bioactivation of drugs that cause hepatotoxicity through the formation of reactive metabolites. The use of drugs needs to be monitored to avoid pharmacokinetic drug interactions.

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

Cited by 3 publications

References 42 publications

Pharmacokinetic and Pharmacodynamic Drug–Drug Interactions: Research Methods and Applications

Pharmacokinetic and Pharmacodynamic Drug–Drug Interactions: Research Methods and Applications

Synthesis and Evaluation of ePSMA-DM1: A New Theranostic Small-Molecule Drug Conjugate (T-SMDC) for Prostate Cancer

Pharmacokinetic Drug-Drug Interactions: A Systematic Review of the Cytochrome P450 (CYP) Isoenzyme 3A4

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