Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.

Article Details

Citation

Fontana E, Dansette PM, Poli SM

Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.

Curr Drug Metab. 2005 Oct;6(5):413-54.

PubMed ID
16248836 [ View in PubMed
]
Abstract

The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
IsoniazidCytochrome P450 1A2ProteinHumans
Unknown
Not AvailableDetails
IsoniazidCytochrome P450 2C19ProteinHumans
Unknown
Not AvailableDetails
IsoniazidCytochrome P450 2C8ProteinHumans
Unknown
Not AvailableDetails
IsoniazidCytochrome P450 3A4ProteinHumans
Unknown
Not AvailableDetails
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AmprenavirCytochrome P450 3A4Ki (nM)260N/AN/ADetails
AmprenavirCytochrome P450 3A5Ki (nM)200N/AN/ADetails
ClarithromycinCytochrome P450 3A4Ki (nM)5490N/AN/ADetails
ClopidogrelCytochrome P450 2B6Ki (nM)500N/AN/ADetails
ClopidogrelCytochrome P450 2B6Ki (nM)1100N/AN/ADetails
DiclofenacCytochrome P450 3A4Ki (nM)1640000N/AN/ADetails
DiltiazemCytochrome P450 3A4Ki (nM)2200N/AN/ADetails
DiltiazemCytochrome P450 3A4Ki (nM)500N/AN/ADetails
EthinylestradiolCytochrome P450 3A4Ki (nM)18000N/AN/ADetails
IndinavirCytochrome P450 3A4Ki (nM)480N/AN/ADetails
IrinotecanCytochrome P450 3A4Ki (nM)24000N/AN/ADetails
IsoniazidCytochrome P450 1A2Ki (nM)56000N/AN/ADetails
IsoniazidCytochrome P450 2C19Ki (nM)10000N/AN/ADetails
LopinavirCytochrome P450 3A4Ki (nM)410N/AN/ADetails
LopinavirCytochrome P450 3A4Ki (nM)1000N/AN/ADetails
MetoclopramideCytochrome P450 2D6Ki (nM)960N/AN/ADetails
MifepristoneCytochrome P450 3A4Ki (nM)4700N/AN/ADetails
ParoxetineCytochrome P450 2D6Ki (nM)4850N/AN/ADetails
PhencyclidineCytochrome P450 2B6Ki (nM)10000N/AN/ADetails
RaloxifeneCytochrome P450 3A4Ki (nM)9900N/AN/ADetails
ResveratrolCytochrome P450 3A4Ki (nM)20000N/AN/ADetails
RitonavirCytochrome P450 3A4Ki (nM)100N/AN/ADetails
RitonavirCytochrome P450 3A5Ki (nM)120N/AN/ADetails
SaquinavirCytochrome P450 3A4Ki (nM)170N/AN/ADetails
SuprofenCytochrome P450 2C9Ki (nM)3700N/AN/ADetails
TacrineCytochrome P450 1A2Ki (nM)1940N/AN/ADetails
TamoxifenCytochrome P450 2B6Ki (nM)900N/AN/ADetails
TamoxifenCytochrome P450 3A4Ki (nM)200N/AN/ADetails
ThiotepaCytochrome P450 2B6Ki (nM)50000N/AN/ADetails
ThiotepaCytochrome P450 2B6Ki (nM)3800N/AN/ADetails
ThiotepaCytochrome P450 2B6Ki (nM)2200N/AN/ADetails
TiclopidineCytochrome P450 2B6Ki (nM)200N/AN/ADetails
TiclopidineCytochrome P450 2B6Ki (nM)800N/AN/ADetails
TiclopidineCytochrome P450 2C19Ki (nM)87000N/AN/ADetails
Tienilic acidCytochrome P450 2C9Ki (nM)4300N/AN/ADetails
VerapamilCytochrome P450 3A4Ki (nM)5100N/AN/ADetails
VerapamilCytochrome P450 3A4Ki (nM)1390N/AN/ADetails
VerapamilCytochrome P450 3A4Ki (nM)6460N/AN/ADetails
VerapamilCytochrome P450 3A4Ki (nM)2970N/AN/ADetails
ZileutonCytochrome P450 1A2Ki (nM)117000N/AN/ADetails
ZileutonCytochrome P450 1A2Ki (nM)66000N/AN/ADetails
ZileutonCytochrome P450 1A2Ki (nM)98200N/AN/ADetails