Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by azelnidipine and manidipine

Ikemura, Noriaki; Yamaori, Satoshi; Kobayashi, Chisato; Kamijo, Shinobu; Murayama, Norie; Yamazaki, Hiroshi; Ohmori, Shigeru

doi:10.1016/j.cbi.2019.04.005

Cited by 15 publications

(4 citation statements)

References 39 publications

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“…The inhibitory mechanism analysis results suggested that amlodipine and nifedipine inhibited the metabolism of vonoprazan by primarily competitive with some non-competitive inhibition. A similar inhibition mechanism has been reported for the effect that amlodipine exerts on CYP2J2 enzyme activity (a relatively high component of competitive inhibition) (Ikemura et al, 2019).…”

Section: Molecular Docking Prediction Of Amlodipine and Vonoprazansupporting

confidence: 73%

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Shi¹,

Dai²,

Cai³

et al. 2022

Front. Pharmacol.

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As a novel acid-suppressing drug, vonoprazan shows the potential to replace traditional proton-pump inhibitors. With its widespread use, some adverse effects that require further study have emerged due to drug–drug interactions. Our study is the first experiment that evaluated the drug–drug interactions of eleven common cardiovascular drugs that inhibit vonoprazan metabolism in vitro and in vivo. Rat liver microsome incubation and molecular simulation docking were applied to explore the inhibition mechanism. Amlodipine and nifedipine showed inhibitory effects on vonoprazan metabolism in both rat and human liver microsomes in the first evaluation part in vitro. The inhibition mechanism analysis results demonstrated that amlodipine and nifedipine might inhibit the metabolism of vonoprazan by a mixed type of competitive and non-competitive inhibition. However, the pharmacokinetic data of the vonoprazan prototype revealed that amlodipine affected vonoprazan in vivo while nifedipine did not. Thus, more attention should be paid when amlodipine is prescribed with vonoprazan. Furthermore, the changes in its carboxylic acid metabolites MI hinted at a complex situation. Molecular simulation suggested the CYP2B6 enzyme may contribute more to this than CYP3A4, and further inhibitory experiments preliminarily verified this speculation. In conclusion, the use of vonoprazan with cardiovascular drugs, especially amlodipine, should receive particular attention in clinical prescriptions.

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Section: Molecular Docking Prediction Of Amlodipine and Vonoprazansupporting

confidence: 73%

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Shi¹,

Dai²,

Cai³

et al. 2022

Front. Pharmacol.

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“…The CYP4F2 inhibitors reported to date are 17-octadecynoic acid (17-ODYA) 3,15,19) and HET0016. 15,20) 17-ODYA was first characterized as a suicide inhibitor of leukotriene B 4 ω-hydroxylase including CYP4F in polymorphonuclear leukocytes. 21) On the other hand, HET0016 was developed as a selective inhibitor of arachidonic acid ω-hydroxylase.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition Studies The luciferin-4F2/3 O-dealkylase activity of recombinant CYP4F2 was determined according to our previous report, 15) with a minor modification. Briefly, an incubation mixture consisted of CYP4F2 Supersomes (20 pmol/mL), potassium phosphate buffer (50 mM, pH 7.4), luciferin-4F2/3 (5 µM), sesamin (0-2.5 µM), and an NADPH-generating system (0.5 mM NADP, 10 mM glucose 6-phosphate, 10 mM magnesium chloride, and 1 unit/mL glucose-6-phosphate dehydrogenase) in a final volume of 200 µL.…”

Section: Methodsmentioning

confidence: 99%

<i>In Vitro</i> Inhibitory Effects of Sesamin on CYP4F2 Activity

Watanabe

Yamaori

Kamijo

et al. 2020

Biological & Pharmaceutical Bulletin

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Sesamin is a major lignan in sesame seeds, and a recent meta-analysis of controlled trials indicated that sesamin intake decreases blood pressure. The antihypertensive effect of sesamin has been suggested to be due to sesamin-mediated suppression of 20-hydroxyeicosatetraenoic acid production catalyzed by CYP4F2. However, the detailed mechanism underlying inhibition of CYP4F2 function by sesamin remains unclear. In this study, the effects of sesamin on catalytic activity of CYP4F2 were investigated in vitro. Sesamin inhibited luciferin-4F2/3 O-dealkylase activity of recombinant human CYP4F2 with an IC 50 value of 0.381 µM. When preincubated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) for 20 min, sesamin potentiated the inhibition of CYP4F2 activity. Moreover, kinetic analysis of the inactivation revealed that sesamin showed a preincubation time-and concentration-dependent inhibition of CYP4F2 activity yielding a maximal inactivation rate constant (k inact) value of 0.354 min 1 and half-maximal inhibitory concentration (K I) value of 1.12 µM. The inactivation of CYP4F2 by sesamin required NADPH. These results indicated that sesamin is a mechanism-based inactivator of human CYP4F2.

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“…were corrected using MOE software (Chemical Computing Group, Inc., Montreal, Canada) [37]. Next, hydrogens were added to AChE and BChE and partial charges were calculated using the Amber10: EHT forcefield [38]. The active pocket was established using the binding site of the co-crystallized AChE ligand E2020.…”

Section: Molecular Dockingmentioning

confidence: 99%

The Cholinesterase Inhibitory Properties of Stephaniae Tetrandrae Radix

et al. 2020

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Stephaniae tetrandrae radix (STR) is a commonly used traditional Chinese medicine in alleviating edema by inducing diuresis. In the clinic, STR extracts or its components are widely used in the treatment of edema, dysuria, and rheumatism for the regulation of water metabolism. Furthermore, STR has been used in treating emotional problems for years by combining with other Chinese herbs. However, the material basis and mechanism of STR on the nervous system have not been revealed. Here, the main components of STR extracts with different extracting solvents were identified, including three major alkaloids, i.e., cyclanoline, fangchinoline, and tetrandrine. The cholinesterase inhibitory activity of STR extracts and its alkaloids was determined using the Ellman assay. Both cyclanoline and fangchinoline showed acetylcholinesterase (AChE) inhibitory activity, demonstrating noncompetitive enzyme inhibition. In contrast, tetrandrine did not show enzymatic inhibition. The synergism of STR alkaloids with huperzine A or donepezil was calculated by the median-effect principle. The drug combination of fangchinoline–huperzine A or donepezil synergistically inhibited AChE, having a combination index (CI) < 1 at Fa = 0.5. Furthermore, the molecular docking results showed that fangchinoline bound with AChE residues in the peripheral anionic site, and cyclanoline bound with AChE residues in the peripheral anionic site, anionic site, and catalytic site. In parallel, cyclanoline bound with butyrylcholinesterase (BChE) residues in the anionic site, catalytic site, and aromatic site. The results support that fangchinoline and cyclanoline, alkaloids derived from STR, could account for the anti-AChE function of STR. Thus, STR extract or its alkaloids may potentially be developed as a therapeutic strategy for Alzheimer’s patients.

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Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by azelnidipine and manidipine

Cited by 15 publications

References 39 publications

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

<i>In Vitro</i> Inhibitory Effects of Sesamin on CYP4F2 Activity

The Cholinesterase Inhibitory Properties of Stephaniae Tetrandrae Radix

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