Prediction of Drug-Drug Interactions based on Time-Dependent Inhibition from High Throughput Screening of Cytochrome P450 3A4 Inhibition

Sekiguchi, Nobuo; Higashida, Atsuko; Kato, Motohiro; Nabuchi, Yoshiaki; Mitsui, Toshio; Takanashi, Koichi; Aso, Yoshinori; Ishigai, Masaki

doi:10.2133/dmpk.24.500

Cited by 37 publications

(31 citation statements)

References 37 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The identity of reactive metabolites of ritonavir, however, remains unknown. Furthermore, the results of other studies argued against the mechanism-based CYP3A4 inhibition 9 or indicated that ritonavir acts as a competitive [10] or mixed competitive-noncompetitive inactivator of CYP3A4 [11–13]. …”

Section: Interaction Of Cyp3a4 With Ritonavirmentioning

confidence: 99%

Ritonavir Analogues as a Probe for Deciphering the Cytochrome P450 3A4 Inhibitory Mechanism

Sevrioukova¹,

Poulos

2014

CTMC

View full text Add to dashboard Cite

Inactivation of human drug-metabolizing cytochrome P450 3A4 (CYP3A4) could lead to serious adverse events such as drug-drug interactions and toxicity. However, when properly controlled, CYP3A4 inhibition may be beneficial as it can improve clinical efficacy of co-administered therapeutics that otherwise are quickly metabolized by CYP3A4. Currently, the CYP3A4 inhibitor ritonavir and its derivative cobicistat are prescribed to HIV patients as pharmacoenhancers. Both drugs were designed based on the chemical structure/activity relationships rather than the CYP3A4 crystal structure. To unravel the structural basis of CYP3A4 inhibition, we compared the binding modes of ritonavir and ten analogues using biochemical, mutagenesis and x-ray crystallography techniques. This review summarizes our findings on the relative contribution of the heme-ligating moiety, side chains and the terminal group of ritonavir-like molecules to the ligand binding process, and highlights strategies for a structure-guided design of CYP3A4 inactivators.

show abstract

Section: Interaction Of Cyp3a4 With Ritonavirmentioning

confidence: 99%

Ritonavir Analogues as a Probe for Deciphering the Cytochrome P450 3A4 Inhibitory Mechanism

Sevrioukova¹,

Poulos

2014

CTMC

View full text Add to dashboard Cite

show abstract

“…Using [I] u /K i,u ratios-i.e., the unbound plasma concentration of the inhibitory metabolite, [I] u , divided by the equilibrium constant for inhibition of warfarin 7-hydroxylation in human liver (HL) microsomes (HLM), normalized to the amount of free inhibitor available in those microsomes, (K i,u )-we predicted the minor AMIO metabolite, N,Ndidesethylamiodarone (DDEA) to be the culprit most likely to induce the hypocoagulation effect seen when AMIO is coadministered with warfarin (McDonald et al, 2012). Of course, [I] u /K i,u ratios are most useful in predicting the inhibitor efficiency of purely reversible inhibitors, and there is conflicting evidence in the literature as to whether AMIO and/or its primary metabolite, N-monodesethylamiodarone (MDEA) can act as irreversible inhibitors of various P450 isozymes, including CYP2C9 (Ohyama et al, 2000;Obach et al, 2007;Berry and Zhao, 2008;Mori et al, 2009;Sekiguchi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

McDonald

Rettie

2015

Drug Metab Dispos

View full text Add to dashboard Cite

In this study, IC 50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I] u /K i,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (K I = 0.46 mM, k inact = 0.030 minute 21 ), while MDEA was a moderate inactivator of both CYP2D6 (K I = 2.7 mM, k inact = 0.018 minute 21) and CYP3A4 (K I = 2.6 mM, k inact = 0.016 minute 21). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex.Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs.

show abstract

“…In a previous study, crude extracts of 78 herbal medicines that exhibit inhibitory effects on CYP3A4 and CYP2D6 were found to be involved in the metabolism of numerous synthetic drugs (Sekiguchi et al, 2009). This study found that rutaecarpine can inhibit the activities of several types of CYPs, namely CYP1A2, CYP2C9, CYP2C19 and CYP2E1, indicating that more than one metabolite of rutaecarpine can be generated in a multiple-oxidation reaction.…”

Section: Discussionmentioning

confidence: 99%

Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine

Zhang

Zhai

et al. 2015

Xenobiotica

View full text Add to dashboard Cite

1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 μM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb-drug interactions, providing important information for predicting drug-induced hepatotoxicity.

show abstract

Prediction of Drug-Drug Interactions based on Time-Dependent Inhibition from High Throughput Screening of Cytochrome P450 3A4 Inhibition

Cited by 37 publications

References 37 publications

Ritonavir Analogues as a Probe for Deciphering the Cytochrome P450 3A4 Inhibitory Mechanism

Ritonavir Analogues as a Probe for Deciphering the Cytochrome P450 3A4 Inhibitory Mechanism

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine

Contact Info

Product

Resources

About