InAADR

Protein Information

Protein Name: Cytochrome P450 3A4 (P08684)
Gene Name: CYP3A4
Description:
PDB ID: 1TQN
Protein Family: PF00067, PS00086
Protein Category: Enzyme

This panel provides drug-protein interaction and their ADRs along with references

Interacting Drugs Toxicity Mechanism Reference
Acetaminophen Hepatotoxicity Particularly at high doses@ cytochrome P-450 enzymes--especially CYP1A2@ CYP2E1@ and isoforms of CYP3A--convert APAP to a reactive quinone form@ N-acetyl-p-benzoquinone imine (NAPQI)@that covalently binds to cellular macromolecules and also causes production of reactive oxygen species@ and leads to acetaminophen-induced hepatotoxicity. [ ADR Type 1 ] Toxicology Protecting liver from painkiller's lethal dose
Amiodarone Bradycardia Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension@ bradycardia@ and decreased cardiac output [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Amiodarone Rhabdomyolysis Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Amitriptyline Bradycardia Amiodarone should be used with caution in patients receiving ?-receptor blocking agents (e.g.@ propranolol@ a CYP3A4 inhibitor) or calcium channel antagonists (e.g.@ verapamil@ a CYP3A4 substrate@ and diltiazem@ a CYP3A4 inhibitor) because of the possible potentiation of bradycardia@ sinus arrest@ and AV block; if necessary@ amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Amitriptyline Elevated Creatinine Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine@ despite reduction in dose of cyclosporine [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Amitriptyline Ineffective Inhibition Of Platelet Aggregation Clopidogrel@ an inactive thienopyridine prodrug@ is metabolized in the liver by CYP3A4 to an active metabolite A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Amitriptyline Rhabdomyolysis Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Carbamazepine Hepatotoxicity The formation of chemically reactive metabolites from carbamazepine (CBZ) in the presence of mouse and human liver microsomes@which is cytochrome P450 dependent@has been investigated using cytotoxicity and irreversible binding of radiolabelled compound as quantitative end-points. [ ADR Type 2 ] An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro
Clonidine Clinical Failure Clozapine inhibits CYP3A4 enzyme activity@thus decreases the plasma concentrations of tricyclic antidepressants@which may lead to clinical failure. [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Dehydrated Alcohol Apap Toxicity APAP toxicity is increased in both humans and rodents by pretreatment with various inducers of CYP gene expression@ including ethanol@ an inducer of CYP2E and CYP3A isoforms (12@ 13)@ and phenobarbital (PB)@ a well-known inducer of CYP2B@ CYP3A@ and other isoforms [ ADR Type 4 ] Toxicology Protecting liver from painkiller's lethal dose
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
Enalapril Hepatotoxicity Enalapril@ quinapril and fosinopril can also underGO P450 3A-dependent bioactivation and require maintenance of glutathione status for detoxification@ and that captopril causes cytotoxicity independent of cytochrome P450 metabolism
Ethinyl Estradiol Hepatotoxicity PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover@ PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs. [ ADR Type 2 ] Environmental xenobiotics and the antihormones cyproterone acetate and spironolactone use the nuclear hormone pregnenolone X receptor to activate the CYP3A23 hormone response element
Felbamate Hepatotoxicity Felbamate appears to induce the activity of CYP3A4@ which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. [ ADR Type 2 ] A mechanistic approach to antiepileptic drug interactions
Flutamide Hepatotoxicity Flutamide is toxic to rat hepatocytes as a result of the cytochrome P450 (3A and also 1A)-mediated formation of electrophilic metabolites@ whose damaging effects are further aggravated by the inhibitory effect of flutamide on mitochondrial respiration and ATP formation
Indinavir Increasing Adverse Effects Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4 Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug@ which could increase or prolong its therapeutic and adverse effects [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Ketoconazole Dangerous Side Effects Terfenadine inhibits CYP3A4 enzyme activity@ thus reduces clearance of ketoconazole that is CYP3A4 substrate and causes dangerous side effects [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Nefazodone Hepatotoxicity The metabolism of NEF and OH-NEF to each of their active metabolites is catalysed mainly by CYP3A4@ which is in agreement with clinical reports of drug--drug interactions of nefazodone with substrates and inhibitors of CYP3A4 [ ADR Type 2 ] Human CYP3A4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes
Olanzapine Clinical Failure Olanzapine inhibits CYP3A4 enzyme activity@ thus decrease the plasma concentrations of tricyclic antidepressants@which may lead to clinical failure [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Phenobarbital Apap Toxicity APAP toxicity is increased in both humans and rodents by pretreatment with various inducers of CYP gene expression@ including ethanol@ an inducer of CYP2E and CYP3A isoforms (12@ 13)@ and phenobarbital (PB)@ a well-known inducer of CYP2B@ CYP3A@ and other isoforms. [ ADR Type 4 ] Toxicology Protecting liver from painkiller's lethal dose
Phenytoin Enhanced Clearance Phenytoin increases the activity of CYP3A4@ leading in enhanced clearance of cisapride and sometimes clinical failure [ ADR Type 4 ] Interactions between anticonvulsant and psychoactive drugs
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
Propranolol Bradycardia Concomitant using of adrenaline and propranolol produces marked inhibition of CYP3A4@ which leads to significant high blood pressure@slow heart beat@atrioventricular block [ ADR Type 4 ] Failure of propranolol to prevent tilt-evoked systemic vasodilatation, adrenaline release, and neurocardiogenic syncope
Propranolol Low Blood Pressure Concomitant using of monoamine oxidase inhibitor and propranolol produces marked inhibition of CYP3A4@ which leads to very low blood pressure. [ ADR Type 4 ] Eletriptan issues Headache
Rifampicin Enhanced Clearance Induction increases the activity of CYP3A4@ leading in enhanced clearance of cisapride and sometimes clinical failure [ ADR Type 4 ] Hepatic failure and encephalopathy attributed to an interaction between acetaminophen and rifampicin
Risperidone Clinical Failure Risperidone inhibits CYP3A4 enzyme activity@thus decreases the plasma concentrations of tricyclic antidepressants@which may lead to clinical failure. [ ADR Type 4 ] Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs
Ritonavir Dizziness Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea@ dizziness@ hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir@ the combination should be used with caution and a lower dose of trazodone should be considered. [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Ritonavir Hypotension Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea@ dizziness@ hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir@ the combination should be used with caution and a lower dose of trazodone should be considered. [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Ritonavir Nausea Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea@ dizziness@ hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir@ the combination should be used with caution and a lower dose of trazodone should be considered. [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Ritonavir Syncope Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea@ dizziness@ hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir@ the combination should be used with caution and a lower dose of trazodone should be considered. [ ADR Type 4 ] Use of terfenadine and contraindicated drugs
Troglitazone Hepatotoxicity The cytochrome P450 (CYP) inhibitors furafylline (CYP1A1/2)@ omeprazole (CYP2C19)@ ketoconazole (CYP3A4)@ and sulfaphenazole (CYP2C9) had no inhibitory effect on the TGZ metabolism suggesting that several P450s may play a role in the TGZ metabolic pathway [ ADR Type 2 ] Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo Evidence for novel biotransformation pathways involving quinone

InAADR: Drug-Protein-ADRs database