GEFITINIB PHARMACOKINETICS PATHWAY (PW:0000870)
Description
Gefitinib belongs to a class of tyrosine kinase inhibitors (TKI) designed to compete with ATP for binding into the ATP binding pocket of mutated or over-expressed receptor and thus inhibit its tyrosine kinase activity and the signaling events downstream of it. Gefitinib along with erlotinib have been used to target epidermal growth factor receptor, Egfr. Gefitinib, presented here, was among the first and the most widely used TKI for use in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). NSCLC is a major cause of cancer mortality accounting for ~80% of all cases, the remaining 20% being attributable to the small-cell lung cancer type (SCLC). Mutations in Egfr are among several well documented contributors to non-small cell lung cancer (NSCLC). They remove an autoinhibitory effect and lead to increase activity even in the absence of ligand binding. Mutations that render the receptor constitutively active also confer higher affinity for the TKI drugs. Gefitinib is primarily metabolized by CYP3A4 and also by CYP3A5, CYP2D6 and the extrahepatic CYP1A1. The drug has been shown to inhibit the activity of CYP2C19 as well as CYP2D6 but the clinical relevance of these findings is however questioned. Several metabolites are being produced; O-desmethyl-derivative (M523595) appears to be the main one resulting from CYP2D6 activity. The CYP enzymes involved in the metabolism of gefitinib and erlotinib have been characterized in human liver and intestinal microsomes (the human genes are shown). Gefitinib and metabolites are disposed off through the action of ABCG2 and to a lesser extent ABCB1 human efflux transporters (human genes are shown). Gefitinib metabolism has also been shown in rats and dogs but the identity of the enzymes involved remains to be established. It is of note that the drug appears to be extensively metabolized by rats, followed by dogs and humans and that the metabolites produced are more similar between dogs and human than between either species and rat. Polymorphism in CYP3A4, CYP3A5 and CYP2D6 has been reported; for CYP3A5 and CYP2D6 it can have serious consequences for drug metabolism, particularly in Caucasians. The efficiency of gefitinib and other TKI is lost within one year of treatment due to acquired resistance. Secondary mutations in Egfr interfere with TKI binding and promote constitutive activation. In addition, amplification of Met oncogene which normally does not engage Egfr members, also leads to increased activation of the receptor and appears to involve Erbb3. Met amplification can lead to increased activation of downstream signaling pathways independent of Egfr; both Egfr and Met mediated signaling impinge upon the same intracellular cascades. The eventually acquired resistance to TKI and the involvement of other altered pathways in NSCLC, has prompted the development of other drugs for the treatment of the disease, including second generation TKI.
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Pathway Diagram:
Genes in Pathway:
G
Abcb1a ATP binding cassette subfamily B member 1A
ISO RGD PMID:19733976 RGD:5135288
NCBI chr 4:25,357,467...25,529,941
G
Abcg2 ATP binding cassette subfamily G member 2
ISO RGD PMID:19733976 RGD:5135288
NCBI chr 4:87,676,241...87,802,757
G
Cyp1a1 cytochrome P450, family 1, subfamily a, polypeptide 1
ISO RGD PMID:19733976 RGD:5135288
NCBI chr 8:58,096,021...58,102,130
G
Cyp2d4 cytochrome P450, family 2, subfamily d, polypeptide 4
ISO RGD PMID:19733976 RGD:5135288
NCBI chr 7:113,882,584...113,891,754
G
Cyp3a2 cytochrome P450, family 3, subfamily a, polypeptide 2
ISO RGD PMID:19733976 RGD:5135288
NCBI chr12:9,207,978...9,230,064
G
Cyp3a9 cytochrome P450, family 3, subfamily a, polypeptide 9
ISO RGD PMID:19733976 RGD:5135288
NCBI chr12:16,806,222...16,846,428
Pathway Gene Annotations
Disease Annotations Associated with Genes in the gefitinib pharmacokinetics pathway
Abcb1a acquired immunodeficiency syndrome , acute lymphoblastic leukemia , adrenocortical carcinoma , allergic rhinitis , Alzheimer's disease , Anthracycline-induced Cardiotoxicity , antisocial personality disorder , asthma , autism spectrum disorder , Behcet's disease , Breast Neoplasms , cannabis abuse , cannabis dependence , carcinoma , cardiomyopathy , Chemical and Drug Induced Liver Injury , Chronic Hepatitis C , chronic myeloid leukemia , colorectal adenocarcinoma , Colorectal Neoplasms , congenital heart disease , COVID-19 , Critical Illness , Crohn's disease , cryoglobulinemia , diarrhea , diffuse large B-cell lymphoma , disease of cellular proliferation , disease of mental health , Disease Progression , drug dependence , Drug Overdose , Drug-induced Neutropenia , Drug-Related Side Effects and Adverse Reactions , encephalitis , end stage renal disease , Endotoxemia , Eosinophilia , epilepsy , Escherichia Coli Infections , Esophageal Neoplasms , Experimental Arthritis , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Experimental Mammary Neoplasms , familial adenomatous polyposis , familial hyperlipidemia , familial mediterranean fever , familial temporal lobe epilepsy 3 , Femur Head Necrosis , Fetal Growth Retardation , genetic disease , Genetic Predisposition to Disease , Genetic Translocation , Germ Cell and Embryonal Neoplasms , head and neck squamous cell carcinoma , heart disease , Helicobacter Infections , Hematologic Neoplasms , hepatocellular carcinoma , hereditary breast ovarian cancer syndrome , heroin dependence , human immunodeficiency virus infectious disease , idiopathic generalized epilepsy , Inflammation , inflammatory bowel disease 13 , invasive ductal carcinoma , kidney disease , Kidney Neoplasms , Latent Tuberculosis , lung non-small cell carcinoma , malaria , metabolic dysfunction-associated steatotic liver disease , Nasal Polyps , nasal type extranodal NK/T-cell lymphoma , Nausea , Neoplasm Metastasis , nephroblastoma , nervous system disease , neuroblastoma , neutropenia , obstructive sleep apnea , opiate dependence , Orthostatic Hypotension , ovarian cancer , Ovarian Neoplasms , Pain , Parkinson's disease , perinatal necrotizing enterocolitis , peripheral nervous system disease , pleomorphic xanthoastrocytoma , Poisoning , Postoperative Pain , pulmonary tuberculosis , renal cell carcinoma , Reperfusion Injury , rheumatoid arthritis , secondary Parkinson disease , ST Elevation Myocardial Infarction , status epilepticus , temporal lobe epilepsy , toxic encephalopathy , type 2 diabetes mellitus , ulcerative colitis , visual epilepsy , Vomiting Abcg2 acute lymphoblastic leukemia , acute megakaryocytic leukemia , acute myeloid leukemia , adenoma , autism spectrum disorder , autosomal dominant polycystic kidney disease , B-Cell Chronic Lymphocytic Leukemia , B-cell lymphoma , breast carcinoma , Breast Neoplasms , cardiomyopathy , chronic myeloid leukemia , Colorectal Neoplasms , congestive heart failure , diabetes mellitus , diarrhea , diffuse large B-cell lymphoma , Drug-Related Side Effects and Adverse Reactions , erythropoietic protoporphyria , Experimental Arthritis , Experimental Diabetes Mellitus , Experimental Mammary Neoplasms , genetic disease , gout , head and neck squamous cell carcinoma , hereditary breast ovarian cancer syndrome , hyperuricemia , Liver Injury , multiple myeloma , nervous system disease , Ovarian Neoplasms , primary biliary cholangitis , renal cell carcinoma , Reperfusion Injury , rheumatoid arthritis , secondary hyperparathyroidism , status epilepticus , T-cell acute lymphoblastic leukemia , toxic encephalopathy , type 2 diabetes mellitus Cyp1a1 acute kidney failure , Acute Lung Injury , acute lymphoblastic leukemia , acute myeloid leukemia , allergic contact dermatitis , allergic disease , ankylosing spondylitis , Arteritis , asthma , atopic dermatitis , autism spectrum disorder , Bardet-Biedl syndrome , Behcet's disease , biliary tract cancer , Birth Weight , Bloom syndrome , Bradycardia , breast cancer , Breast Neoplasms , bronchitis , Cardiac Fibrosis , Cardiomegaly , Chemical and Drug Induced Liver Injury , Chronic Bronchitis , Chronic Intermittent Hypoxia , chronic myeloid leukemia , chronic obstructive pulmonary disease , clubfoot , colitis , colorectal cancer , contact dermatitis , cystic fibrosis , diabetes mellitus , Digestive System Neoplasms , dilated cardiomyopathy , Drug Eruptions , end stage renal disease , endometrial cancer , endometriosis , esophageal cancer , esophagus squamous cell carcinoma , Experimental Diabetes Mellitus , Experimental Liver Neoplasms , Fetal Growth Retardation , gallbladder cancer , genetic disease , Graves' disease , Hamartoma , head and neck cancer , heart disease , Hematuria , hepatocellular carcinoma , Hepatomegaly , Hyperoxia , Hyperoxic Lung Injury , hypertension , Hypertriglyceridemia , hypertrophic cardiomyopathy , hypospadias , Inflammation , Jaundice , Keshan disease , Kidney Neoplasms , Liver Reperfusion Injury , long QT syndrome , lung cancer , Lung Injury , male infertility , Metabolic Side Effects of Drugs and Substances , Micronuclei, Chromosome-Defective , multiple myeloma , Nematode Infections , nephritis , Occupational Diseases , oral cavity cancer , oral squamous cell carcinoma , Parkinson's disease , Parkinsonism , periodontitis , peripheral vascular disease , pneumonia , polycystic ovary syndrome , porphyria cutanea tarda , Prenatal Exposure Delayed Effects , prostate cancer , Prostatic Neoplasms , psoriasis , psoriatic arthritis , pulmonary hypertension , Pulmonary Hypertension, Hypoxia-Induced , reactive arthritis , renal cell carcinoma , schizophrenia , Sepsis , Sinus Tachycardia , Sjogren's syndrome , Spontaneous Abortions , stomach cancer , systemic lupus erythematosus , type 2 diabetes mellitus , urinary bladder cancer , Ventricular Remodeling Cyp2d4 acute kidney failure , acute lymphoblastic leukemia , acute myeloid leukemia , alcohol dependence , Alzheimer's disease , amphetamine abuse , asthma , autism spectrum disorder , autoimmune hepatitis , basal ganglia disease , Bradycardia , Breast Neoplasms , Chemical and Drug Induced Liver Injury , Chronic Hepatitis C , cognitive disorder , Coma , common variable immunodeficiency 4 , Developmental Delay with Variable Intellectual Impairment and Behavioral Abnormalities , Drug Overdose , Drug-Induced Dyskinesia , Drug-Related Side Effects and Adverse Reactions , Dysmenorrhea , dystonia , epilepsy with generalized tonic-clonic seizures , Experimental Liver Cirrhosis , extrapyramidal and movement disease , genetic disease , head and neck squamous cell carcinoma , intellectual disability , interstitial nephritis , major depressive disorder , Manganese Poisoning , multiple myeloma , Muscle Rigidity , Occupational Diseases , opiate dependence , Parkinson's disease , Poor Drug Metabolism, CYP2D6-Related , Prenatal Exposure Delayed Effects , Prostatic Neoplasms , rhinitis , sexual health disorder , substance-related disorder , traumatic brain injury , Tremor , Weight Gain Cyp3a2 anxiety disorder , breast cancer , Breast Neoplasms , Chemical and Drug Induced Liver Injury , cholestasis , end stage renal disease , familial mediterranean fever , Familial Prostate Cancer , genetic disease , hepatitis C , Inflammation , osteosarcoma , ovarian carcinoma , pleomorphic xanthoastrocytoma , Prostatic Neoplasms , Subarachnoid Hemorrhage , Torsades de Pointes , type 2 diabetes mellitus , VITAMIN D-DEPENDENT RICKETS, TYPE 3 Cyp3a9 acute lymphoblastic leukemia , autism spectrum disorder , B-lymphoblastic leukemia/lymphoma , Chemotherapy-Induced Febrile Neutropenia , chronic myeloid leukemia , Drug-Induced Leukopenia , Drug-induced Neutropenia , essential hypertension , Experimental Liver Cirrhosis , genetic disease , kidney disease , myasthenia gravis , Myeloid Leukemia, Chronic-Phase , nephrosis , Pediatric Crohn's Disease , pleomorphic xanthoastrocytoma , Prostatic Neoplasms , Reperfusion Injury , thrombosis , toxic encephalopathy
acquired immunodeficiency syndrome Abcb1a acute kidney failure Cyp1a1 , Cyp2d4 Acute Lung Injury Cyp1a1 acute lymphoblastic leukemia Abcb1a , Abcg2 , Cyp1a1 , Cyp2d4 , Cyp3a9 acute megakaryocytic leukemia Abcg2 acute myeloid leukemia Abcg2 , Cyp1a1 , Cyp2d4 adenoma Abcg2 adrenocortical carcinoma Abcb1a alcohol dependence Cyp2d4 allergic contact dermatitis Cyp1a1 allergic disease Cyp1a1 allergic rhinitis Abcb1a Alzheimer's disease Abcb1a , Cyp2d4 amphetamine abuse Cyp2d4 ankylosing spondylitis Cyp1a1 Anthracycline-induced Cardiotoxicity Abcb1a antisocial personality disorder Abcb1a anxiety disorder Cyp3a2 Arteritis Cyp1a1 asthma Abcb1a , Cyp1a1 , Cyp2d4 atopic dermatitis Cyp1a1 autism spectrum disorder Abcb1a , Abcg2 , Cyp1a1 , Cyp2d4 , Cyp3a9 autoimmune hepatitis Cyp2d4 autosomal dominant polycystic kidney disease Abcg2 B-Cell Chronic Lymphocytic Leukemia Abcg2 B-cell lymphoma Abcg2 B-lymphoblastic leukemia/lymphoma Cyp3a9 Bardet-Biedl syndrome Cyp1a1 basal ganglia disease Cyp2d4 Behcet's disease Abcb1a , Cyp1a1 biliary tract cancer Cyp1a1 Birth Weight Cyp1a1 Bloom syndrome Cyp1a1 Bradycardia Cyp1a1 , Cyp2d4 breast cancer Cyp1a1 , Cyp3a2 breast carcinoma Abcg2 Breast Neoplasms Abcb1a , Abcg2 , Cyp1a1 , Cyp2d4 , Cyp3a2 bronchitis Cyp1a1 cannabis abuse Abcb1a cannabis dependence Abcb1a carcinoma Abcb1a Cardiac Fibrosis Cyp1a1 Cardiomegaly Cyp1a1 cardiomyopathy Abcb1a , Abcg2 Chemical and Drug Induced Liver Injury Abcb1a , Cyp1a1 , Cyp2d4 , Cyp3a2 Chemotherapy-Induced Febrile Neutropenia Cyp3a9 cholestasis Cyp3a2 Chronic Bronchitis Cyp1a1 Chronic Hepatitis C Abcb1a , Cyp2d4 Chronic Intermittent Hypoxia Cyp1a1 chronic myeloid leukemia Abcb1a , Abcg2 , Cyp1a1 , Cyp3a9 chronic obstructive pulmonary disease Cyp1a1 clubfoot Cyp1a1 cognitive disorder Cyp2d4 colitis Cyp1a1 colorectal adenocarcinoma Abcb1a colorectal cancer Cyp1a1 Colorectal Neoplasms Abcb1a , Abcg2 Coma Cyp2d4 common variable immunodeficiency 4 Cyp2d4 congenital heart disease Abcb1a congestive heart failure Abcg2 contact dermatitis Cyp1a1 COVID-19 Abcb1a Critical Illness Abcb1a Crohn's disease Abcb1a cryoglobulinemia Abcb1a cystic fibrosis Cyp1a1 Developmental Delay with Variable Intellectual Impairment and Behavioral Abnormalities Cyp2d4 diabetes mellitus Abcg2 , Cyp1a1 diarrhea Abcb1a , Abcg2 diffuse large B-cell lymphoma Abcb1a , Abcg2 Digestive System Neoplasms Cyp1a1 dilated cardiomyopathy Cyp1a1 disease of cellular proliferation Abcb1a disease of mental health Abcb1a Disease Progression Abcb1a drug dependence Abcb1a Drug Eruptions Cyp1a1 Drug Overdose Abcb1a , Cyp2d4 Drug-Induced Dyskinesia Cyp2d4 Drug-Induced Leukopenia Cyp3a9 Drug-induced Neutropenia Abcb1a , Cyp3a9 Drug-Related Side Effects and Adverse Reactions Abcb1a , Abcg2 , Cyp2d4 Dysmenorrhea Cyp2d4 dystonia Cyp2d4 encephalitis Abcb1a end stage renal disease Abcb1a , Cyp1a1 , Cyp3a2 endometrial cancer Cyp1a1 endometriosis Cyp1a1 Endotoxemia Abcb1a Eosinophilia Abcb1a epilepsy Abcb1a epilepsy with generalized tonic-clonic seizures Cyp2d4 erythropoietic protoporphyria Abcg2 Escherichia Coli Infections Abcb1a esophageal cancer Cyp1a1 Esophageal Neoplasms Abcb1a esophagus squamous cell carcinoma Cyp1a1 essential hypertension Cyp3a9 Experimental Arthritis Abcb1a , Abcg2 Experimental Diabetes Mellitus Abcb1a , Abcg2 , Cyp1a1 Experimental Liver Cirrhosis Abcb1a , Cyp2d4 , Cyp3a9 Experimental Liver Neoplasms Cyp1a1 Experimental Mammary Neoplasms Abcb1a , Abcg2 extrapyramidal and movement disease Cyp2d4 familial adenomatous polyposis Abcb1a familial hyperlipidemia Abcb1a familial mediterranean fever Abcb1a , Cyp3a2 Familial Prostate Cancer Cyp3a2 familial temporal lobe epilepsy 3 Abcb1a Femur Head Necrosis Abcb1a Fetal Growth Retardation Abcb1a , Cyp1a1 gallbladder cancer Cyp1a1 genetic disease Abcb1a , Abcg2 , Cyp1a1 , Cyp2d4 , Cyp3a2 , Cyp3a9 Genetic Predisposition to Disease Abcb1a Genetic Translocation Abcb1a Germ Cell and Embryonal Neoplasms Abcb1a gout Abcg2 Graves' disease Cyp1a1 Hamartoma Cyp1a1 head and neck cancer Cyp1a1 head and neck squamous cell carcinoma Abcb1a , Abcg2 , Cyp2d4 heart disease Abcb1a , Cyp1a1 Helicobacter Infections Abcb1a Hematologic Neoplasms Abcb1a Hematuria Cyp1a1 hepatitis C Cyp3a2 hepatocellular carcinoma Abcb1a , Cyp1a1 Hepatomegaly Cyp1a1 hereditary breast ovarian cancer syndrome Abcb1a , Abcg2 heroin dependence Abcb1a human immunodeficiency virus infectious disease Abcb1a Hyperoxia Cyp1a1 Hyperoxic Lung Injury Cyp1a1 hypertension Cyp1a1 Hypertriglyceridemia Cyp1a1 hypertrophic cardiomyopathy Cyp1a1 hyperuricemia Abcg2 hypospadias Cyp1a1 idiopathic generalized epilepsy Abcb1a Inflammation Abcb1a , Cyp1a1 , Cyp3a2 inflammatory bowel disease 13 Abcb1a intellectual disability Cyp2d4 interstitial nephritis Cyp2d4 invasive ductal carcinoma Abcb1a Jaundice Cyp1a1 Keshan disease Cyp1a1 kidney disease Abcb1a , Cyp3a9 Kidney Neoplasms Abcb1a , Cyp1a1 Latent Tuberculosis Abcb1a Liver Injury Abcg2 Liver Reperfusion Injury Cyp1a1 long QT syndrome Cyp1a1 lung cancer Cyp1a1 Lung Injury Cyp1a1 lung non-small cell carcinoma Abcb1a major depressive disorder Cyp2d4 malaria Abcb1a male infertility Cyp1a1 Manganese Poisoning Cyp2d4 metabolic dysfunction-associated steatotic liver disease Abcb1a Metabolic Side Effects of Drugs and Substances Cyp1a1 Micronuclei, Chromosome-Defective Cyp1a1 multiple myeloma Abcg2 , Cyp1a1 , Cyp2d4 Muscle Rigidity Cyp2d4 myasthenia gravis Cyp3a9 Myeloid Leukemia, Chronic-Phase Cyp3a9 Nasal Polyps Abcb1a nasal type extranodal NK/T-cell lymphoma Abcb1a Nausea Abcb1a Nematode Infections Cyp1a1 Neoplasm Metastasis Abcb1a nephritis Cyp1a1 nephroblastoma Abcb1a nephrosis Cyp3a9 nervous system disease Abcb1a , Abcg2 neuroblastoma Abcb1a neutropenia Abcb1a obstructive sleep apnea Abcb1a Occupational Diseases Cyp1a1 , Cyp2d4 opiate dependence Abcb1a , Cyp2d4 oral cavity cancer Cyp1a1 oral squamous cell carcinoma Cyp1a1 Orthostatic Hypotension Abcb1a osteosarcoma Cyp3a2 ovarian cancer Abcb1a ovarian carcinoma Cyp3a2 Ovarian Neoplasms Abcb1a , Abcg2 Pain Abcb1a Parkinson's disease Abcb1a , Cyp1a1 , Cyp2d4 Parkinsonism Cyp1a1 Pediatric Crohn's Disease Cyp3a9 perinatal necrotizing enterocolitis Abcb1a periodontitis Cyp1a1 peripheral nervous system disease Abcb1a peripheral vascular disease Cyp1a1 pleomorphic xanthoastrocytoma Abcb1a , Cyp3a2 , Cyp3a9 pneumonia Cyp1a1 Poisoning Abcb1a polycystic ovary syndrome Cyp1a1 Poor Drug Metabolism, CYP2D6-Related Cyp2d4 porphyria cutanea tarda Cyp1a1 Postoperative Pain Abcb1a Prenatal Exposure Delayed Effects Cyp1a1 , Cyp2d4 primary biliary cholangitis Abcg2 prostate cancer Cyp1a1 Prostatic Neoplasms Cyp1a1 , Cyp2d4 , Cyp3a2 , Cyp3a9 psoriasis Cyp1a1 psoriatic arthritis Cyp1a1 pulmonary hypertension Cyp1a1 Pulmonary Hypertension, Hypoxia-Induced Cyp1a1 pulmonary tuberculosis Abcb1a reactive arthritis Cyp1a1 renal cell carcinoma Abcb1a , Abcg2 , Cyp1a1 Reperfusion Injury Abcb1a , Abcg2 , Cyp3a9 rheumatoid arthritis Abcb1a , Abcg2 rhinitis Cyp2d4 schizophrenia Cyp1a1 secondary hyperparathyroidism Abcg2 secondary Parkinson disease Abcb1a Sepsis Cyp1a1 sexual health disorder Cyp2d4 Sinus Tachycardia Cyp1a1 Sjogren's syndrome Cyp1a1 Spontaneous Abortions Cyp1a1 ST Elevation Myocardial Infarction Abcb1a status epilepticus Abcb1a , Abcg2 stomach cancer Cyp1a1 Subarachnoid Hemorrhage Cyp3a2 substance-related disorder Cyp2d4 systemic lupus erythematosus Cyp1a1 T-cell acute lymphoblastic leukemia Abcg2 temporal lobe epilepsy Abcb1a thrombosis Cyp3a9 Torsades de Pointes Cyp3a2 toxic encephalopathy Abcb1a , Abcg2 , Cyp3a9 traumatic brain injury Cyp2d4 Tremor Cyp2d4 type 2 diabetes mellitus Abcb1a , Abcg2 , Cyp1a1 , Cyp3a2 ulcerative colitis Abcb1a urinary bladder cancer Cyp1a1 Ventricular Remodeling Cyp1a1 visual epilepsy Abcb1a VITAMIN D-DEPENDENT RICKETS, TYPE 3 Cyp3a2 Vomiting Abcb1a Weight Gain Cyp2d4
