LOSARTAN PHARMACOKINETICS PATHWAY (PW:0001463)
Description
Losartan is a selective and competitive non-peptide antagonist of angiotensin II receptor type 1 (Agtr1) used in the treatment of hypertension and heart failure. Angiotensin II (AngII) is one of several and probably the most potent peptide generated by the renin-angiotensin cascade. AngII signals through two receptor types to elicit distinct responses. The Agtr1 mediated pathway is involved in vasoconstriction, proliferation, hormone release and fluid homeostasis. The powerful but potentially harmful effects elicited by Agtr1 are counterbalanced by the Agtr2 mediated signaling. This pathway promotes vasodilation, NO release and growth inhibition. The Agtr1 mediated pathway is the better understood one. Losartan is one of eight Agrt1 antagonists collectively known as ARBs that are clinically available; losartan is the first marketed and the most frequently prescribed. ARBs are effective antihypertensive agents; however, they exhibit differences in terms of pharmacokinetics properties and pleiotropic effects. The losartan parent compound has a rather moderate affinity for the receptor. Following rapid absorption, losartan is metabolized to the more potent metabolite E3174 via the E3179 intermediate. The affinity of E3174 for the Agtr1 is 20- to 30-times greater than that of losartan. Other minor metabolites are also produced that are less active than the parent compound. In humans, the main cytochrome P450 enzymes involved in losartan phase I biotransformation are CYP3A4 and CYP2C9 with CYP2C8 also contributing. The phase II biotransformation (glucuronidation) is carried out by the UGT1A1 and UGT2B7 enzymes. The ABCB1 member is involved in the efflux of losartan and metabolites. The Agtr1 receptor is a G-protein coupled receptor (GPCR) that couples to the Galphaq of heterotrimeric G proteins that activates phospholipase C; subsequent events lead to the activation of the protein kinase C (PKC) intracellular pathway. In the context of Agtr1, transactivation of epidermal growth factor/neuregulin and of Erk1/2 signaling as well as activation of the Jak-Stat pathway have been reported. The allelic variants of CYP2C9, depending on the identity of the variant, exhibit decreased formation of E3174 or seem to not affect the antihypertensive response. However, further investigations of this and other enzymes in the losartan pharmacokinetics pathway are necessary in order the assess the effect(s) of genetic variation on the therapeutic efficacy of the drug. Losartan, in addition to its antihypertensive effects, may also slow down the progression of diabetic nephropathy, reduce renal disease progression in patients with type 2 diabetes (T2D) and decrease peripheral insulin resistance in T2D patients and animal models. Losartan also exhibits uricosuric action, possibly via inhibition of urate transporter 1, Slc22a12 known as URAT1 - one of several apical urate/anion exchangers involved in the reabsorption of urate in the proximal tubules. While some adverse side effects of ARBs have been reported, they are relatively rare.
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Pathway Diagram:
Genes in Pathway:
G
Abcb1a
ATP binding cassette subfamily B member 1A
ISO
RGD
PMID:10725273
RGD:7364967
NCBI chr 4:26,312,403...26,488,456
Ensembl chr 4:26,312,409...26,397,135
G
Cyp2c79
cytochrome P450, family 2, subfamily c, polypeptide 79
ISO
RGD
PMID:23118328
RGD:7364964
G
Cyp3a2
cytochrome P450, family 3, subfamily a, polypeptide 2
ISO
RGD
PMID:21666702
RGD:7364965
NCBI chr12:14,321,771...14,343,886
Ensembl chr12:14,321,771...14,343,857
G
Ugt1a1
UDP glucuronosyltransferase family 1 member A1
ISO
RGD
PMID:18674515
RGD:7364966
NCBI chr 9:96,249,143...96,256,264
Ensembl chr 9:96,144,786...96,256,264
G
Ugt1a2
UDP glucuronosyltransferase 1 family, polypeptide A2
ISO
RGD
PMID:18674515
RGD:7364966
NCBI chr 9:96,239,019...96,256,264
Ensembl chr 9:96,144,786...96,256,264
G
Ugt2b7
UDP glucuronosyltransferase family 2 member B7
ISO
RGD
PMID:18674515
RGD:7364966
NCBI chr14:21,251,535...21,274,451
Ensembl chr14:21,251,535...21,274,451
Pathway Gene Annotations
Disease Annotations Associated with Genes in the losartan 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 , 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 , Vomiting Cyp2c79 acute lymphoblastic leukemia , autism spectrum disorder , chronic obstructive pulmonary disease , Drug-Induced Leukopenia , Drug-induced Neutropenia , Drug-Related Side Effects and Adverse Reactions , end stage renal disease , hepatocellular carcinoma , kidney disease , nervous system disease , peripheral nervous system disease , renal hypertension , Rhabdomyolysis , Rhabdomyolysis, Cerivastatin-Induced Cyp3a2 alcohol dependence , Alcoholic Liver Diseases , 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 , pleomorphic xanthoastrocytoma , Prostatic Neoplasms , Subarachnoid Hemorrhage , Torsades de Pointes , type 2 diabetes mellitus , VITAMIN D-DEPENDENT RICKETS, TYPE 3 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 , genetic disease , Gilbert syndrome , Gram-Negative Bacterial Infections , hematopoietic system disease , hepatitis B , Hereditary Hyperbilirubinemia , Hodgkin's lymphoma , Hyperbilirubinemia, Transient Familial Neonatal , hyperthyroidism , Inflammation , Jaundice , Joubert syndrome 22 , kernicterus , lung non-small cell carcinoma , myeloid leukemia , Neonatal Hyperbilirubinemia , neutropenia , ovarian cancer , Perlman syndrome , Polyuria , small cell carcinoma , Starvation , type 1 diabetes mellitus , type 2 diabetes mellitus Ugt1a2 bilirubin metabolic disorder , Crigler Najjar Syndrome, Type 1 , Crigler Najjar Syndrome, Type 2 , Crigler-Najjar syndrome , genetic disease , Gilbert syndrome , Hyperbilirubinemia, Transient Familial Neonatal , Joubert syndrome 22 , Perlman syndrome , schizophrenia Ugt2b7 autism spectrum disorder , urinary bladder cancer
acquired immunodeficiency syndrome Abcb1a acute kidney failure Ugt1a1 Acute Liver Failure Ugt1a1 acute lymphoblastic leukemia Abcb1a , Cyp2c79 adrenocortical carcinoma Abcb1a alcohol dependence Cyp3a2 Alcoholic Liver Diseases Cyp3a2 allergic rhinitis Abcb1a Alzheimer's disease Abcb1a Anthracycline-induced Cardiotoxicity Abcb1a antisocial personality disorder Abcb1a anxiety disorder Cyp3a2 asthma Abcb1a Audiogenic Epilepsy Abcb1a autism spectrum disorder Abcb1a , Cyp2c79 , Ugt1a1 , Ugt2b7 Behcet's disease Abcb1a bilirubin metabolic disorder Ugt1a1 , Ugt1a2 breast cancer Cyp3a2 , Ugt1a1 Breast Neoplasms Abcb1a , Cyp3a2 cannabis abuse Abcb1a cannabis dependence Abcb1a carcinoma Abcb1a cardiomyopathy Abcb1a Chemical and Drug Induced Liver Injury Abcb1a , Cyp3a2 , Ugt1a1 cholecystolithiasis Ugt1a1 cholelithiasis Ugt1a1 cholestasis Cyp3a2 , Ugt1a1 Chronic Hepatitis C Abcb1a chronic myeloid leukemia Abcb1a chronic obstructive pulmonary disease Cyp2c79 colorectal adenocarcinoma Abcb1a Colorectal Neoplasms Abcb1a congenital heart disease Abcb1a contact dermatitis Ugt1a1 COVID-19 Abcb1a Crigler Najjar Syndrome, Type 1 Ugt1a1 , Ugt1a2 Crigler Najjar Syndrome, Type 2 Ugt1a1 , Ugt1a2 Crigler-Najjar syndrome Ugt1a1 , Ugt1a2 Critical Illness Abcb1a Crohn's disease Abcb1a , Ugt1a1 cryoglobulinemia Abcb1a diarrhea Abcb1a diffuse large B-cell lymphoma Abcb1a disease of cellular proliferation Abcb1a disease of mental health Abcb1a Disease Progression Abcb1a drug dependence Abcb1a Drug Overdose Abcb1a Drug-Induced Leukopenia Cyp2c79 Drug-induced Neutropenia Abcb1a , Cyp2c79 , Ugt1a1 Drug-Related Side Effects and Adverse Reactions Abcb1a , Cyp2c79 , Ugt1a1 encephalitis Abcb1a ENCEPHALOPATHY, ACUTE TRANSIENT Abcb1a end stage renal disease Abcb1a , Cyp2c79 , Cyp3a2 endometrial cancer Ugt1a1 Endotoxemia Abcb1a Eosinophilia Abcb1a epilepsy Abcb1a Escherichia Coli Infections Abcb1a Esophageal Neoplasms Abcb1a Experimental Arthritis Abcb1a Experimental Diabetes Mellitus Abcb1a Experimental Liver Cirrhosis Abcb1a 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 genetic disease Ugt1a1 , Ugt1a2 Genetic Predisposition to Disease Abcb1a Genetic Translocation Abcb1a Germ Cell and Embryonal Neoplasms Abcb1a Gilbert syndrome Ugt1a1 , Ugt1a2 Gram-Negative Bacterial Infections Ugt1a1 head and neck squamous cell carcinoma Abcb1a heart disease Abcb1a Helicobacter Infections Abcb1a Hematologic Neoplasms Abcb1a hematopoietic system disease Ugt1a1 hepatitis B Ugt1a1 hepatitis C Cyp3a2 hepatocellular carcinoma Abcb1a , Cyp2c79 hereditary breast ovarian cancer syndrome Abcb1a Hereditary Hyperbilirubinemia Ugt1a1 heroin dependence Abcb1a Hodgkin's lymphoma Ugt1a1 human immunodeficiency virus infectious disease Abcb1a Hyperbilirubinemia, Transient Familial Neonatal Ugt1a1 , Ugt1a2 hyperthyroidism Ugt1a1 Idiopathic Generalized Epilepsy Abcb1a Inflammation Abcb1a , Cyp3a2 , Ugt1a1 inflammatory bowel disease 13 Abcb1a invasive ductal carcinoma Abcb1a Jaundice Ugt1a1 Joubert syndrome 22 Ugt1a1 , Ugt1a2 kernicterus Ugt1a1 kidney disease Abcb1a , Cyp2c79 Kidney Neoplasms Abcb1a Latent Tuberculosis Abcb1a lung non-small cell carcinoma Abcb1a , Ugt1a1 malaria Abcb1a metabolic dysfunction-associated steatotic liver disease Abcb1a myeloid leukemia Ugt1a1 Nasal Polyps Abcb1a nasal type extranodal NK/T-cell lymphoma Abcb1a Nausea Abcb1a Neonatal Hyperbilirubinemia Ugt1a1 Neoplasm Metastasis Abcb1a nephroblastoma Abcb1a nervous system disease Abcb1a , Cyp2c79 neuroblastoma Abcb1a neutropenia Abcb1a , Ugt1a1 obstructive sleep apnea Abcb1a opiate dependence Abcb1a Orthostatic Hypotension Abcb1a osteosarcoma Cyp3a2 ovarian cancer Abcb1a , Ugt1a1 ovarian carcinoma Cyp3a2 Pain Abcb1a Parkinson's disease Abcb1a perinatal necrotizing enterocolitis Abcb1a peripheral nervous system disease Abcb1a , Cyp2c79 Perlman syndrome Ugt1a1 , Ugt1a2 pleomorphic xanthoastrocytoma Abcb1a , Cyp3a2 Poisoning Abcb1a Polyuria Ugt1a1 Postoperative Pain Abcb1a Prostatic Neoplasms Cyp3a2 pulmonary tuberculosis Abcb1a renal cell carcinoma Abcb1a renal hypertension Cyp2c79 Reperfusion Injury Abcb1a Rhabdomyolysis Cyp2c79 Rhabdomyolysis, Cerivastatin-Induced Cyp2c79 rheumatoid arthritis Abcb1a schizophrenia Ugt1a2 secondary Parkinson disease Abcb1a small cell carcinoma Ugt1a1 ST Elevation Myocardial Infarction Abcb1a Starvation Ugt1a1 status epilepticus Abcb1a Subarachnoid Hemorrhage Cyp3a2 temporal lobe epilepsy Abcb1a Torsades de Pointes Cyp3a2 toxic encephalopathy Abcb1a type 1 diabetes mellitus Ugt1a1 type 2 diabetes mellitus Abcb1a , Cyp3a2 , Ugt1a1 ulcerative colitis Abcb1a urinary bladder cancer Ugt2b7 VITAMIN D-DEPENDENT RICKETS, TYPE 3 Cyp3a2 Vomiting Abcb1a