Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.

Article Details

Citation

Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.

Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7563-8.

PubMed ID
10377455 [ View in PubMed
]
Abstract

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
SuprofenProstaglandin G/H synthase 1ProteinHumans
Yes
Inhibitor
Details
SuprofenProstaglandin G/H synthase 2ProteinHumans
Yes
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AcetaminophenProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
Acetylsalicylic acidProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
Acetylsalicylic acidProstaglandin G/H synthase 2Ki (nM)7500N/AN/ADetails
CarprofenProstaglandin G/H synthase 2Ki (nM)4300N/AN/ADetails
CelecoxibProstaglandin G/H synthase 2Ki (nM)830N/AN/ADetails
CelecoxibProstaglandin G/H synthase 2Ki (nM)340N/AN/ADetails
DiflunisalProstaglandin G/H synthase 2Ki (nM)8200N/AN/ADetails
DiflunisalProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
EtodolacProstaglandin G/H synthase 2Ki (nM)2200N/AN/ADetails
EtodolacProstaglandin G/H synthase 2Ki (nM)940N/AN/ADetails
FenoprofenProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
FenoprofenProstaglandin G/H synthase 2Ki (nM)5900N/AN/ADetails
FlurbiprofenProstaglandin G/H synthase 2Ki (nM)5500N/AN/ADetails
FlurbiprofenProstaglandin G/H synthase 2Ki (nM)770N/AN/ADetails
IbuprofenProstaglandin G/H synthase 2Ki (nM)7200N/AN/ADetails
IbuprofenProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
IndomethacinProstaglandin G/H synthase 2Ki (nM)1000N/AN/ADetails
IndomethacinProstaglandin G/H synthase 2Ki (nM)130N/AN/ADetails
KetoprofenProstaglandin G/H synthase 2Ki (nM)2900N/AN/ADetails
KetoprofenProstaglandin G/H synthase 2Ki (nM)240N/AN/ADetails
Meclofenamic acidProstaglandin G/H synthase 2Ki (nM)700N/AN/ADetails
Meclofenamic acidProstaglandin G/H synthase 2Ki (nM)200N/AN/ADetails
Mefenamic acidProstaglandin G/H synthase 2Ki (nM)2900N/AN/ADetails
Mefenamic acidProstaglandin G/H synthase 2Ki (nM)1300N/AN/ADetails
MeloxicamProstaglandin G/H synthase 2Ki (nM)2100N/AN/ADetails
MeloxicamProstaglandin G/H synthase 2Ki (nM)230N/AN/ADetails
MesalazineProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
NabumetoneProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
NaproxenProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
Niflumic acidProstaglandin G/H synthase 2Ki (nM)5400N/AN/ADetails
Niflumic acidProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
NimesulideProstaglandin G/H synthase 2Ki (nM)1900N/AN/ADetails
NimesulideProstaglandin G/H synthase 2Ki (nM)390N/AN/ADetails
ResveratrolProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
RofecoxibProstaglandin G/H synthase 2Ki (nM)840N/AN/ADetails
RofecoxibProstaglandin G/H synthase 2Ki (nM)310N/AN/ADetails
Salicylic acidProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
SulfasalazineProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
SulindacProstaglandin G/H synthase 2Ki (nM)>10000N/AN/ADetails
SuprofenProstaglandin G/H synthase 2Ki (nM)8700N/AN/ADetails
SuprofenProstaglandin G/H synthase 2Ki (nM)8300N/AN/ADetails
TolmetinProstaglandin G/H synthase 2Ki (nM)820N/AN/ADetails
TolmetinProstaglandin G/H synthase 2Ki (nM)1300N/AN/ADetails