| Protein Name: | Cytochrome P450 2C9 (P11712) |
|---|---|
| Gene Name: | CYP2C9 |
| Description: | |
| PDB ID: | 1OG2 |
| Protein Family: | PF00067, PS00086 |
| Protein Category: | Enzyme |
This panel provides drug-protein interaction and their ADRs along with references
| Interacting Drugs | Toxicity | Mechanism | Reference |
|---|---|---|---|
| Amiodarone | Fatal Bleeding | Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days@ the dose of the anticoagulant should be reduced by one-third to one-half@ and prothrombin times should be monitored closely. [ ADR Type 4 ] | Warfarin interactions with chloral hydrate and glutethimide |
| Diclofenac | Hepatotoxicity | The biotransformation of diclofenac to M2 is P450 2C9-dependent@ whereas metabolism of the drug to M1 and M3 involves mainly P450 3A4. Although P450s 2C9 and 3A4 both catalyze the bioactivation of diclofenac@ P450 2C9 is capable of producing the benzoquinone imine intermediate at lower drug concentrations which may be more clinically relevant. [ ADR Type 2 ] | Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac |
| Glipizide | Hypoglycaemia | Leu359 (CYP2C9) mutation is responsible for hypoglycaemia | |
| Losartan | Decreased Antihypertensive Effect | Individuals homozyGOus for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates Consistent with the modulation of enzyme activity by genetic and other factors@ wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates Finally@it decreased antihypertensive effect of losartan [ ADR Type 1 ] | Cytochrome P4502C9: an enzyme of major importance in human drug metabolism |
| Phenytoin | Hepatotoxicity | These results suggest that P450 2C19 and other forms from the 2C and 3A subfamilies may be targets as well as catalysts of drug-protein adduct formation from phenytoin [ ADR Type 2 ] | Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation |
| Phenytoin | Phenytoin Toxicity | Leu359 (CYP2C9) mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype. [ ADR Type 1 ] | Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C93 allele |
| Ticrynafen | Hepatotoxicity | Tienilic acid-reactive metabolite(s) specifically bound to P450 2C9@ and experiments with yeast expressing active isolated P450s showed that P450 2C9 was responsible for tienilic acid-reactive metabolite(s) production Results of qualitative and quantitative covalent binding of tienilic acid metabolite(s) to human liver microsomes were then compared to those obtained with two drugs leading to direct toxic hepatitis@ namely@ acetaminophen and chloroform [ ADR Type 2 ] | Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity |
| Tolbutamide | Hypoglycaemia | Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates.Consistent with the modulation of enzyme activity by genetic and other factors@ wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates.Finally@it leads to hypoglycaemia. [ ADR Type 1 ] | Cytochrome P4502C9: an enzyme of major importance in human drug metabolism |
| Valproic Acid | Hepatotoxicity | CYP3A4@ the isoform usually associated with induction by anticonvulsants cannot be responsible for the enhanced 4-ene-VPA formation that occurs during polytherapy. Instead@ enhanced activity in vivo likely results from induction of CYP2C9. [ ADR Type 2 ] | Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans |
| Warfarin | Haemorrhage | There is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications. [ ADR Type 1 ] | Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications |
| Zafirlukast | Significant Increase In The Mean Auc And Half-Life Of S-Warfarin | In a drug interaction study in 16 healthy male volunteers@ coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. [ ADR Type 4 ] | Warfarin interactions with chloral hydrate and glutethimide |
This panel provides information on drug category