Cytochrome P450 enzymes: a review on drug metabolizing enzyme inhibition studies in drug discovery and development

Bioanalysis ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 1355-1378
Author(s):  
Siva Nageswara Rao Gajula ◽  
Megha Sajakumar Pillai ◽  
Gananadhamu Samanthula ◽  
Rajesh Sonti
Keyword(s):  
Cytochrome P450 ◽  
Drug Discovery ◽  
Enzyme Inhibition ◽  
In Vitro Study ◽  
Cytochrome P450 Enzymes ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Cyp Enzymes ◽  
Cyp Inhibition

Assessment of drug candidate's potential to inhibit cytochrome P450 (CYP) enzymes remains crucial in pharmaceutical drug discovery and development. Both direct and time-dependent inhibition of drug metabolizing CYP enzymes by the concomitant administered drug is the leading cause of drug–drug interactions (DDIs), resulting in the increased toxicity of the victim drug. In this context, pharmaceutical companies have grown increasingly diligent in limiting CYP inhibition liabilities of drug candidates in the early stages and examining risk assessments throughout the drug development process. This review discusses different strategies and decision-making processes for assessing the drug–drug interaction risks by enzyme inhibition and lays particular emphasis on in vitro study designs and interpretation of CYP inhibition data in a stage-appropriate context.

scholarly journals In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qun Zhang ◽  
Zengqiang Qu ◽  
Yanqing Zhou ◽  
Jin Zhou ◽  
Junwei Yang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Liver Microsomes ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Drug Drug Interaction ◽  
Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

scholarly journals Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 409 ◽  
Author(s):  
Violetta Mohos ◽  
Eszter Fliszár-Nyúl ◽  
Beáta Lemli ◽  
Balázs Zoltán Zsidó ◽  
Csaba Hetényi ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
In Vitro Study ◽  
Limited Information ◽  
Cytochrome P450 Enzymes ◽  
Flavonoid Aglycones ◽  
Pharmacokinetic Interactions

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

scholarly journals The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

2020 ◽  
Vol 72 (6) ◽  
pp. 1685-1694 ◽  
Author(s):  
Przemysław J. Danek ◽  
Jacek Wójcikowski ◽  
Władysława A. Daniel
Keyword(s):  
Cytochrome P450 ◽  
Combined Therapy ◽  
Liver Microsomes ◽  
Atypical Neuroleptics ◽  
Cytochrome P450 Enzymes ◽  
Cyp Enzymes ◽  
Human Cytochrome ◽  
Competitive Mechanism ◽  
Mixed Mechanism

Abstract Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.

scholarly journals In vitro study on the effect of peucedanol on the activity of cytochrome P450 enzymes

2021 ◽  
Vol 59 (1) ◽  
pp. 937-942
Author(s):  
Cun Zhang ◽  
Yongwei Li ◽  
Changlong Yin ◽  
Jie Zheng ◽  
Guozhi Liu
Keyword(s):  
Cytochrome P450 ◽  
In Vitro Study ◽  
Vitro Study ◽  
Cytochrome P450 Enzymes

scholarly journals A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes in vitro Based on Human-Induced Hepatocytes (hiHeps)

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Li ◽  
Ying-Yuan Lu ◽  
Jun Jia ◽  
Meng Fang ◽  
Lin Zhao ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Evaluation System ◽  
Human Fibroblasts ◽  
Liver Microsomes ◽  
Cytochrome P450 Enzymes ◽  
Cyp Enzymes ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Toxicity Of Drugs

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS–SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.

In vitro study on the effect of ophiopogonin D on the activity of cytochrome P450 enzymes

Xenobiotica ◽  
2020 ◽  
pp. 1-6
Author(s):  
Xiaofei Ji ◽  
Baodong Ding ◽  
Xiaoyou Wu ◽  
Fengyi Liu ◽  
Fengqi Yang
Keyword(s):  
Cytochrome P450 ◽  
In Vitro Study ◽  
Vitro Study ◽  
Cytochrome P450 Enzymes
Sign in / Sign up

Export Citation Format

Share Document