AXITINIB PHARMACOKINETICS PATHWAY (PW:0001124)
Description
Axitinib is a selective inhibitor of vascular endothelial growth factor (VEGF) signaling pathway used in the treatment of renal cell carcinoma and several other tumors. The drug belongs to a class of tyrosine kinase receptor inhibitors (TKI) designed to compete with ATP for binding into the ATP binding pocket of the receptor, thus inhibit its kinase activity and the signaling events downstream of it. Axitinib is selective for VEGF receptor1, 2 and 3; it can also act as a weaker inhibitor for the platelet derived growth factor receptor beta (not shown). VEGF is one of the many target genes of hypoxia inducible factor (Hif) pathway, the master regulator of oxygen homeostasis which is constitutively active in renal cell carcinoma. In the normal Hif pathway, under normoxic conditions the Hif proteins are subject to hydroxylation by prolyl and asparagyl hydroxylases whose own enzymatic activities are oxygen dependent. The modified prolines are recognized by Vhl which then targets Hif for proteosomal degradation. When the levels of oxygen are low, Hif is not modified, translocates to the nucleus where it forms heterodimers with the beta partner to regulate the expression of target genes. Targets include genes involved in glucose and energy homeostasis, erythropoiesis and angiogenesis, among others. Vhl harbors many germline and somatic mutations; most result in loss of function for both alleles. It is believed that specific mutations underlie distinct morbidity and mortality phenotypes. The inability to target Hif for degradation renders the pathway constitutively active regardless oxygen levels. Additional stabilization of Hif appears to be due to mutations in fumarate hydratase (Fh) and succinate dehydrogenase (Sdhb and Sdhd of Sdh complex) enzymes of the citric acid cycle and in the case of Sdh of the electron transport chain as well where it functions as complex II. Either Fh or Sdh mutations affect the necessary modification of Hif under normoxic condition, creating a pseudohypoxic environment that promotes Hif activity even when Vhl might be wild type. Axitinib is one of a number of TKI used in the treatment of renal cell carcinoma; its overall pharmacokinetics are known, but the molecular details are not well characterized. Axitinib is primarily metabolized by phase I biotransformation cytochrome P450 members CYTA34/5 but others such as CYP1a2 and CYP2C19 have also been implicated. The drug is also a substrate for the phase II conjugating enzyme UDP-glucuronosyltransferase (UGT) 1a1. Phase II biotransformation results in more hydrophilic compounds that are easier to eliminate via the bile or urine. Axitinib is also a substrate for the drug transporters ABCB1 and SLCO1B1. There are several side effects associated with axitinib such as GI disturbances, nausea, fatigue and hypertension; GI and skin disturbances appear to be common among the TKI inhibitors used for the treatment of renal cell carcinoma.
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Pathway Diagram:
Genes in Pathway:
G
Abcb1a
ATP binding cassette subfamily B member 1A
ISO
RGD PMID:22170007 RGD:6907361
NCBI chr 4:26,312,403...26,488,456
G
Cyp1a2
cytochrome P450, family 1, subfamily a, polypeptide 2
ISO
RGD PMID:22170007 RGD:6907361
NCBI chr 8:66,971,261...66,978,149
G
Cyp2c6
cytochrome P450, family 2, subfamily C, polypeptide 6
ISO
RGD PMID:22170007 RGD:6907361
NCBI chr 1:247,879,058...247,916,804
G
Cyp3a2
cytochrome P450, family 3, subfamily a, polypeptide 2
ISO
RGD PMID:22170007 RGD:6907361
NCBI chr12:14,321,771...14,343,886
G
Cyp3a9
cytochrome P450, family 3, subfamily a, polypeptide 9
ISO
RGD PMID:22170007 RGD:6907361
NCBI chr12:21,919,955...21,960,160
G
Ugt1a1
UDP glucuronosyltransferase family 1 member A1
ISO
RGD PMID:22170007 RGD:6907361
NCBI chr 9:96,249,143...96,256,264
Pathway Gene Annotations
Disease Annotations Associated with Genes in the axitinib pharmacokinetics pathway
Abcb1a acquired immunodeficiency syndrome , acute lymphoblastic leukemia , adrenocortical carcinoma , allergic rhinitis , Alzheimer's disease , Anthracycline-induced Cardiotoxicity , antisocial personality disorder , asthma , Audiogenic Epilepsy , 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 , ENCEPHALOPATHY, ACUTE TRANSIENT , 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 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 , Pain , Parkinson's disease , perinatal necrotizing enterocolitis , peripheral nervous system disease , 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 , Vomiting Cyp1a2 acute kidney failure , acute lymphoblastic leukemia , Atrophy , autism spectrum disorder , breast cancer , Chemical and Drug Induced Liver Injury , cholestasis , chronic obstructive pulmonary disease , Colorectal Neoplasms , congestive heart failure , depressive disorder , Drug-Related Side Effects and Adverse Reactions , endometrial cancer , Experimental Liver Cirrhosis , Experimental Liver Neoplasms , Growth Disorders , hepatocellular carcinoma , Hepatomegaly , Intestinal Reperfusion Injury , Jaundice , liver cirrhosis , liver disease , Liver Injury , Lung Injury , Lung Neoplasms , metabolic dysfunction-associated steatotic liver disease , Metabolic Side Effects of Drugs and Substances , methemoglobinemia , neural tube defect , Phenacetin O-Deethylase, Deficiency of , porphyria cutanea tarda , Sepsis , splenic disease , Splenomegaly , squamous cell carcinoma , Tardive Dyskinesia , type 2 diabetes mellitus , Vitamin E Deficiency Cyp2c6 Acute Coronary Syndrome , acute kidney failure , alcohol withdrawal syndrome , Allergic Rhinoconjunctivitis , atrial fibrillation , autism spectrum disorder , breast cancer , cardiovascular system disease , Chemical and Drug Induced Liver Injury , dilated cardiomyopathy , Drug Eruptions , Dyslipidemias , end stage renal disease , eosinophilic esophagitis , Experimental Liver Neoplasms , Gastrointestinal Hemorrhage , Genetic Predisposition to Disease , head and neck squamous cell carcinoma , Helicobacter Infections , Hematologic Neoplasms , hepatocellular carcinoma , heroin dependence , invasive aspergillosis , Invasive Fungal Infections , Keshan disease , multiple chemical sensitivity , multiple myeloma , peptic ulcer disease , Plasmodium falciparum malaria , Poor Drug Metabolism, CYP2C19-Related , Poor Metabolism of Proguanil , primary ovarian insufficiency , Prostatic Neoplasms , sickle cell anemia , thrombosis , tuberculosis , type 2 diabetes mellitus Cyp3a2 alcohol dependence , alcohol-associated liver disease , anxiety disorder , breast cancer , Breast Neoplasms , Chemical and Drug Induced Liver Injury , cholestasis , end stage renal disease , familial Mediterranean fever , Familial Prostate Cancer , hepatitis C , Inflammation , osteosarcoma , ovarian carcinoma , 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 , kidney disease , liver cirrhosis , Myeloid Leukemia, Chronic-Phase , nephrosis , oral submucous fibrosis , Pediatric Crohn's Disease , Prostatic Neoplasms , Reperfusion Injury , thrombosis , toxic encephalopathy Ugt1a1 acute kidney failure , Acute Liver Failure , autism spectrum disorder , bilirubin metabolic disorder , breast cancer , Chemical and Drug Induced Liver Injury , cholecystolithiasis , cholelithiasis , cholestasis , contact dermatitis , Crigler Najjar Syndrome, Type 1 , Crigler Najjar Syndrome, Type 2 , Crigler-Najjar syndrome , Crohn's disease , Drug-induced Neutropenia , Drug-Related Side Effects and Adverse Reactions , endometrial cancer , Gallstones , Gilbert syndrome , Gram-Negative Bacterial Infections , hematopoietic system disease , hepatitis B , Hereditary Hyperbilirubinemia , Hodgkin's lymphoma , Hyperbilirubinemia, Transient Familial Neonatal , hyperthyroidism , Inflammation , Jaundice , kernicterus , lung non-small cell carcinoma , myeloid leukemia , Neonatal Hyperbilirubinemia , neutropenia , ovarian cancer , Polyuria , small cell carcinoma , Starvation , type 1 diabetes mellitus , type 2 diabetes mellitus
acquired immunodeficiency syndrome Abcb1a Acute Coronary Syndrome Cyp2c6 acute kidney failure Cyp1a2 , Cyp2c6 , Ugt1a1 Acute Liver Failure Ugt1a1 acute lymphoblastic leukemia Abcb1a , Cyp1a2 , Cyp3a9 adrenocortical carcinoma Abcb1a alcohol dependence Cyp3a2 alcohol withdrawal syndrome Cyp2c6 alcohol-associated liver disease Cyp3a2 allergic rhinitis Abcb1a Allergic Rhinoconjunctivitis Cyp2c6 Alzheimer's disease Abcb1a Anthracycline-induced Cardiotoxicity Abcb1a antisocial personality disorder Abcb1a anxiety disorder Cyp3a2 asthma Abcb1a atrial fibrillation Cyp2c6 Atrophy Cyp1a2 Audiogenic Epilepsy Abcb1a autism spectrum disorder Abcb1a , Cyp1a2 , Cyp2c6 , Cyp3a9 , Ugt1a1 B-lymphoblastic leukemia/lymphoma Cyp3a9 Behcet's disease Abcb1a bilirubin metabolic disorder Ugt1a1 breast cancer Cyp1a2 , Cyp2c6 , Cyp3a2 , Ugt1a1 Breast Neoplasms Abcb1a , Cyp3a2 cannabis abuse Abcb1a cannabis dependence Abcb1a carcinoma Abcb1a cardiomyopathy Abcb1a cardiovascular system disease Cyp2c6 Chemical and Drug Induced Liver Injury Abcb1a , Cyp1a2 , Cyp2c6 , Cyp3a2 , Ugt1a1 Chemotherapy-Induced Febrile Neutropenia Cyp3a9 cholecystolithiasis Ugt1a1 cholelithiasis Ugt1a1 cholestasis Cyp1a2 , Cyp3a2 , Ugt1a1 Chronic Hepatitis C Abcb1a chronic myeloid leukemia Abcb1a , Cyp3a9 chronic obstructive pulmonary disease Cyp1a2 colorectal adenocarcinoma Abcb1a Colorectal Neoplasms Abcb1a , Cyp1a2 congenital heart disease Abcb1a congestive heart failure Cyp1a2 contact dermatitis Ugt1a1 COVID-19 Abcb1a Crigler Najjar Syndrome, Type 1 Ugt1a1 Crigler Najjar Syndrome, Type 2 Ugt1a1 Crigler-Najjar syndrome Ugt1a1 Critical Illness Abcb1a Crohn's disease Abcb1a , Ugt1a1 cryoglobulinemia Abcb1a depressive disorder Cyp1a2 diarrhea Abcb1a diffuse large B-cell lymphoma Abcb1a dilated cardiomyopathy Cyp2c6 disease of cellular proliferation Abcb1a disease of mental health Abcb1a Disease Progression Abcb1a drug dependence Abcb1a Drug Eruptions Cyp2c6 Drug Overdose Abcb1a Drug-Induced Leukopenia Cyp3a9 Drug-induced Neutropenia Abcb1a , Cyp3a9 , Ugt1a1 Drug-Related Side Effects and Adverse Reactions Abcb1a , Cyp1a2 , Ugt1a1 Dyslipidemias Cyp2c6 encephalitis Abcb1a ENCEPHALOPATHY, ACUTE TRANSIENT Abcb1a end stage renal disease Abcb1a , Cyp2c6 , Cyp3a2 endometrial cancer Cyp1a2 , Ugt1a1 Endotoxemia Abcb1a Eosinophilia Abcb1a eosinophilic esophagitis Cyp2c6 epilepsy Abcb1a Escherichia Coli Infections Abcb1a Esophageal Neoplasms Abcb1a essential hypertension Cyp3a9 Experimental Arthritis Abcb1a Experimental Diabetes Mellitus Abcb1a Experimental Liver Cirrhosis Abcb1a , Cyp1a2 , Cyp3a9 Experimental Liver Neoplasms Cyp1a2 , Cyp2c6 Experimental Mammary Neoplasms Abcb1a 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 Gallstones Ugt1a1 Gastrointestinal Hemorrhage Cyp2c6 Genetic Predisposition to Disease Abcb1a , Cyp2c6 Genetic Translocation Abcb1a Germ Cell and Embryonal Neoplasms Abcb1a Gilbert syndrome Ugt1a1 Gram-Negative Bacterial Infections Ugt1a1 Growth Disorders Cyp1a2 head and neck squamous cell carcinoma Abcb1a , Cyp2c6 heart disease Abcb1a Helicobacter Infections Abcb1a , Cyp2c6 Hematologic Neoplasms Abcb1a , Cyp2c6 hematopoietic system disease Ugt1a1 hepatitis B Ugt1a1 hepatitis C Cyp3a2 hepatocellular carcinoma Abcb1a , Cyp1a2 , Cyp2c6 Hepatomegaly Cyp1a2 hereditary breast ovarian cancer syndrome Abcb1a Hereditary Hyperbilirubinemia Ugt1a1 heroin dependence Abcb1a , Cyp2c6 Hodgkin's lymphoma Ugt1a1 human immunodeficiency virus infectious disease Abcb1a Hyperbilirubinemia, Transient Familial Neonatal Ugt1a1 hyperthyroidism Ugt1a1 Idiopathic Generalized Epilepsy Abcb1a Inflammation Abcb1a , Cyp3a2 , Ugt1a1 inflammatory bowel disease 13 Abcb1a Intestinal Reperfusion Injury Cyp1a2 invasive aspergillosis Cyp2c6 invasive ductal carcinoma Abcb1a Invasive Fungal Infections Cyp2c6 Jaundice Cyp1a2 , Ugt1a1 kernicterus Ugt1a1 Keshan disease Cyp2c6 kidney disease Abcb1a , Cyp3a9 Kidney Neoplasms Abcb1a Latent Tuberculosis Abcb1a liver cirrhosis Cyp1a2 , Cyp3a9 liver disease Cyp1a2 Liver Injury Cyp1a2 Lung Injury Cyp1a2 Lung Neoplasms Cyp1a2 lung non-small cell carcinoma Abcb1a , Ugt1a1 malaria Abcb1a metabolic dysfunction-associated steatotic liver disease Abcb1a , Cyp1a2 Metabolic Side Effects of Drugs and Substances Cyp1a2 methemoglobinemia Cyp1a2 multiple chemical sensitivity Cyp2c6 multiple myeloma Cyp2c6 myeloid leukemia Ugt1a1 Myeloid Leukemia, Chronic-Phase Cyp3a9 Nasal Polyps Abcb1a nasal type extranodal NK/T-cell lymphoma Abcb1a Nausea Abcb1a Neonatal Hyperbilirubinemia Ugt1a1 Neoplasm Metastasis Abcb1a nephroblastoma Abcb1a nephrosis Cyp3a9 nervous system disease Abcb1a neural tube defect Cyp1a2 neuroblastoma Abcb1a neutropenia Abcb1a , Ugt1a1 obstructive sleep apnea Abcb1a opiate dependence Abcb1a oral submucous fibrosis Cyp3a9 Orthostatic Hypotension Abcb1a osteosarcoma Cyp3a2 ovarian cancer Abcb1a , Ugt1a1 ovarian carcinoma Cyp3a2 Pain Abcb1a Parkinson's disease Abcb1a Pediatric Crohn's Disease Cyp3a9 peptic ulcer disease Cyp2c6 perinatal necrotizing enterocolitis Abcb1a peripheral nervous system disease Abcb1a Phenacetin O-Deethylase, Deficiency of Cyp1a2 Plasmodium falciparum malaria Cyp2c6 Poisoning Abcb1a Polyuria Ugt1a1 Poor Drug Metabolism, CYP2C19-Related Cyp2c6 Poor Metabolism of Proguanil Cyp2c6 porphyria cutanea tarda Cyp1a2 Postoperative Pain Abcb1a primary ovarian insufficiency Cyp2c6 Prostatic Neoplasms Cyp2c6 , Cyp3a2 , Cyp3a9 pulmonary tuberculosis Abcb1a renal cell carcinoma Abcb1a Reperfusion Injury Abcb1a , Cyp3a9 rheumatoid arthritis Abcb1a secondary Parkinson disease Abcb1a Sepsis Cyp1a2 sickle cell anemia Cyp2c6 small cell carcinoma Ugt1a1 splenic disease Cyp1a2 Splenomegaly Cyp1a2 squamous cell carcinoma Cyp1a2 ST Elevation Myocardial Infarction Abcb1a Starvation Ugt1a1 status epilepticus Abcb1a Subarachnoid Hemorrhage Cyp3a2 Tardive Dyskinesia Cyp1a2 temporal lobe epilepsy Abcb1a thrombosis Cyp2c6 , Cyp3a9 Torsades de Pointes Cyp3a2 toxic encephalopathy Abcb1a , Cyp3a9 tuberculosis Cyp2c6 type 1 diabetes mellitus Ugt1a1 type 2 diabetes mellitus Abcb1a , Cyp1a2 , Cyp2c6 , Cyp3a2 , Ugt1a1 ulcerative colitis Abcb1a VITAMIN D-DEPENDENT RICKETS, TYPE 3 Cyp3a2 Vitamin E Deficiency Cyp1a2 Vomiting Abcb1a
