WARFARIN PHARMACOKINETICS PATHWAY (PW:0000730)
Description
Warfarin, trade name Coumadin, is a widely-used oral anticoagulant drug for the prevention of thrombosis and venous and arterial thromboembolism. It is a synthetic derivative of coumarin-derived dicoumarol. Warfarin is present as a racemic mixture of R and S enantiomers, both active, though not equally, and both metabolized via different routes. The S-warfarin is 3 to 5 times more potent than the R-enantiomer. Warfarin is metabolized, mainly in the liver, by several cytochrome P450 phase I biotransformation enzymes, depending on the enantiomeric form and producing a number of metabolites. S-warfarin is primarily metabolized to 7-hydroxywarfarin by CYP2C9 and to a lesser extent to 6-hydroxywarfarin by the same enzyme. R-warfarin is preferentially metabolized by CYP3A4 to 10-hydroxywarfarin, but other family members, such as CYP1A1 and A2, and CYP2C8, C18 or C19, can also target it. 4-, 7-, and 6- and 8-hydroxywarfarin metabolites are formed by CYP2C18; CYP1A1, A2 and CYP2C8; CYP1A1, A2 and CYP2C19, respectively. The two main enzymes of phase I warfarin biotransformation - CYP2C9 and CYP3A4, are highlighted. 7- and 10-hydroxywarfarin, the two main metabolites of S- and R-warfarin, respectively, act as inhibitors of CYP2C9. Of the phase II biotransformation enzymes, several (UDP)-glucuronosyltransferases (UGTs) process the warfarin metabolites, with various specificities. UGT1A10 glucuronidates 4-, 6-, 7-, and 8-hydroxywarfarin, while UGT1A8 metabolizes 7- and 8-hydroxywarfarin. The two UGTs are extrahepatic intestinal enzymes. Of the hepatic enzymes, UGT1A1 glucuronidates 6-, 7- and 8-hydroxywarfarin while UGT1A9 only metabolizes 8-hydroxywarfarin. In addition to having the broadest specificity, the extrahepatic UGT1A10 has the highest activity - the enzyme is highlighted. Warfarin itself is not subject to the glucuronidation reaction indicating that conjugation of the drug is dependent upon its oxidation. Of all metabolites, 4-hydroxywarfarin is the least modified while 10-hydroxywarfarin does not appear to be subject to glucuronidation. Currently, little is known about sulfonation of warfarin or its derivatives; sulfonation is another type of phase II biotransformation reaction. Warfarin and metabolites are primarily excreted in urine. The biotransformation enzymes, in particular cytochrome P450 members, have a rather broad specificity and are largely not well conserved through evolution. Many of the pharmacokinetics studies have been carried out in human liver microsomes and/or with recombinant human proteins; the human genes are listed (and color coded blue).
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Pathway Diagram:
Genes in Pathway:
G
Cyp1a1
cytochrome P450, family 1, subfamily a, polypeptide 1
ISO
RGD PMID:26655108 RGD:11354883
NCBI chr 8:66,991,940...66,998,014
G
Cyp1a2
cytochrome P450, family 1, subfamily a, polypeptide 2
ISO
RGD PMID:26655108 RGD:11354883
NCBI chr 8:66,971,261...66,978,149
G
Cyp2c11
cytochrome P450, subfamily 2, polypeptide 11
ISO
RGD PMID:26655108 RGD:11354883
NCBI chr 1:246,175,216...246,211,445
G
Cyp2c6
cytochrome P450, family 2, subfamily C, polypeptide 6
ISO
RGD PMID:26655108 RGD:11354883
NCBI chr 1:247,879,058...247,916,804
G
Cyp2c79
cytochrome P450, family 2, subfamily c, polypeptide 79
ISO
RGD PMID:26655108 RGD:11354883
G
Cyp3a2
cytochrome P450, family 3, subfamily a, polypeptide 2
ISO
RGD PMID:26655108 RGD:11354883
NCBI chr12:14,321,771...14,343,886
G
Ugt1a1
UDP glucuronosyltransferase family 1 member A1
ISO
RGD PMID:17921187 RGD:11354886
NCBI chr 9:96,249,143...96,256,264
G
Ugt1a9
UDP glucuronosyltransferase family 1 member A9
ISO
RGD PMID:17921187 RGD:11354886
NCBI chr 9:96,144,786...96,256,264
Pathway Gene Annotations
Disease Annotations Associated with Genes in the warfarin pharmacokinetics pathway
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 , Behcet's disease , biliary tract cancer , Birth Weight , 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 , 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 , 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 , Sepsis , Sinus Tachycardia , Sjogren's syndrome , Spontaneous Abortions , stomach cancer , systemic lupus erythematosus , type 2 diabetes mellitus , urinary bladder cancer , Ventricular Remodeling 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 Cyp2c11 Cardiomegaly , Chemical and Drug Induced Liver Injury , depressive disorder , Diabetes Complications , end stage renal disease , Experimental Liver Cirrhosis , gliosarcoma , head and neck squamous cell carcinoma , hypertension , Prostatic Neoplasms , urinary bladder cancer , Vitamin A 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 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 , 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 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 Ugt1a9 acute kidney failure , Chemical and Drug Induced Liver Injury , cholangiocarcinoma , Crigler-Najjar syndrome , Gilbert syndrome , Leber congenital amaurosis
Acute Coronary Syndrome Cyp2c6 acute kidney failure Cyp1a1 , Cyp1a2 , Cyp2c6 , Ugt1a1 , Ugt1a9 Acute Liver Failure Ugt1a1 Acute Lung Injury Cyp1a1 acute lymphoblastic leukemia Cyp1a1 , Cyp1a2 , Cyp2c79 acute myeloid leukemia Cyp1a1 alcohol dependence Cyp3a2 alcohol withdrawal syndrome Cyp2c6 alcohol-associated liver disease Cyp3a2 allergic contact dermatitis Cyp1a1 allergic disease Cyp1a1 Allergic Rhinoconjunctivitis Cyp2c6 ankylosing spondylitis Cyp1a1 anxiety disorder Cyp3a2 Arteritis Cyp1a1 asthma Cyp1a1 atopic dermatitis Cyp1a1 atrial fibrillation Cyp2c6 Atrophy Cyp1a2 autism spectrum disorder Cyp1a1 , Cyp1a2 , Cyp2c6 , Cyp2c79 , Ugt1a1 Behcet's disease Cyp1a1 biliary tract cancer Cyp1a1 bilirubin metabolic disorder Ugt1a1 Birth Weight Cyp1a1 Bradycardia Cyp1a1 breast cancer Cyp1a1 , Cyp1a2 , Cyp2c6 , Cyp3a2 , Ugt1a1 Breast Neoplasms Cyp1a1 , Cyp3a2 bronchitis Cyp1a1 Cardiac Fibrosis Cyp1a1 Cardiomegaly Cyp1a1 , Cyp2c11 cardiovascular system disease Cyp2c6 Chemical and Drug Induced Liver Injury Cyp1a1 , Cyp1a2 , Cyp2c11 , Cyp2c6 , Cyp3a2 , Ugt1a1 , Ugt1a9 cholangiocarcinoma Ugt1a9 cholecystolithiasis Ugt1a1 cholelithiasis Ugt1a1 cholestasis Cyp1a2 , Cyp3a2 , Ugt1a1 Chronic Bronchitis Cyp1a1 Chronic Intermittent Hypoxia Cyp1a1 chronic myeloid leukemia Cyp1a1 chronic obstructive pulmonary disease Cyp1a1 , Cyp1a2 , Cyp2c79 clubfoot Cyp1a1 colitis Cyp1a1 Colorectal Neoplasms Cyp1a2 congestive heart failure Cyp1a2 contact dermatitis Cyp1a1 , Ugt1a1 Crigler Najjar Syndrome, Type 1 Ugt1a1 Crigler Najjar Syndrome, Type 2 Ugt1a1 Crigler-Najjar syndrome Ugt1a1 , Ugt1a9 Crohn's disease Ugt1a1 cystic fibrosis Cyp1a1 depressive disorder Cyp1a2 , Cyp2c11 Diabetes Complications Cyp2c11 diabetes mellitus Cyp1a1 Digestive System Neoplasms Cyp1a1 dilated cardiomyopathy Cyp1a1 , Cyp2c6 Drug Eruptions Cyp1a1 , Cyp2c6 Drug-Induced Leukopenia Cyp2c79 Drug-induced Neutropenia Cyp2c79 , Ugt1a1 Drug-Related Side Effects and Adverse Reactions Cyp1a2 , Cyp2c79 , Ugt1a1 Dyslipidemias Cyp2c6 end stage renal disease Cyp1a1 , Cyp2c11 , Cyp2c6 , Cyp2c79 , Cyp3a2 endometrial cancer Cyp1a1 , Cyp1a2 , Ugt1a1 endometriosis Cyp1a1 eosinophilic esophagitis Cyp2c6 esophageal cancer Cyp1a1 esophagus squamous cell carcinoma Cyp1a1 Experimental Diabetes Mellitus Cyp1a1 Experimental Liver Cirrhosis Cyp1a2 , Cyp2c11 Experimental Liver Neoplasms Cyp1a1 , Cyp1a2 , Cyp2c6 familial Mediterranean fever Cyp3a2 Familial Prostate Cancer Cyp3a2 Fetal Growth Retardation Cyp1a1 gallbladder cancer Cyp1a1 Gallstones Ugt1a1 Gastrointestinal Hemorrhage Cyp2c6 Genetic Predisposition to Disease Cyp2c6 Gilbert syndrome Ugt1a1 , Ugt1a9 gliosarcoma Cyp2c11 Gram-Negative Bacterial Infections Ugt1a1 Graves' disease Cyp1a1 Growth Disorders Cyp1a2 hamartoma Cyp1a1 head and neck cancer Cyp1a1 head and neck squamous cell carcinoma Cyp2c11 , Cyp2c6 heart disease Cyp1a1 Helicobacter Infections Cyp2c6 Hematologic Neoplasms Cyp2c6 hematopoietic system disease Ugt1a1 Hematuria Cyp1a1 hepatitis B Ugt1a1 hepatitis C Cyp3a2 hepatocellular carcinoma Cyp1a1 , Cyp1a2 , Cyp2c6 , Cyp2c79 Hepatomegaly Cyp1a1 , Cyp1a2 Hereditary Hyperbilirubinemia Ugt1a1 heroin dependence Cyp2c6 Hodgkin's lymphoma Ugt1a1 Hyperbilirubinemia, Transient Familial Neonatal Ugt1a1 Hyperoxia Cyp1a1 Hyperoxic Lung Injury Cyp1a1 hypertension Cyp1a1 , Cyp2c11 hyperthyroidism Ugt1a1 Hypertriglyceridemia Cyp1a1 hypertrophic cardiomyopathy Cyp1a1 hypospadias Cyp1a1 Inflammation Cyp1a1 , Cyp3a2 , Ugt1a1 Intestinal Reperfusion Injury Cyp1a2 invasive aspergillosis Cyp2c6 Invasive Fungal Infections Cyp2c6 Jaundice Cyp1a1 , Cyp1a2 , Ugt1a1 kernicterus Ugt1a1 Keshan disease Cyp1a1 , Cyp2c6 kidney disease Cyp2c79 Kidney Neoplasms Cyp1a1 Leber congenital amaurosis Ugt1a9 liver cirrhosis Cyp1a2 liver disease Cyp1a2 Liver Injury Cyp1a2 Liver Reperfusion Injury Cyp1a1 long QT syndrome Cyp1a1 lung cancer Cyp1a1 Lung Injury Cyp1a1 , Cyp1a2 Lung Neoplasms Cyp1a2 lung non-small cell carcinoma Ugt1a1 male infertility Cyp1a1 metabolic dysfunction-associated steatotic liver disease Cyp1a2 Metabolic Side Effects of Drugs and Substances Cyp1a1 , Cyp1a2 methemoglobinemia Cyp1a2 Micronuclei, Chromosome-Defective Cyp1a1 multiple chemical sensitivity Cyp2c6 multiple myeloma Cyp1a1 , Cyp2c6 myeloid leukemia Ugt1a1 Nematode Infections Cyp1a1 Neonatal Hyperbilirubinemia Ugt1a1 nephritis Cyp1a1 nervous system disease Cyp2c79 neural tube defect Cyp1a2 neutropenia Ugt1a1 Occupational Diseases Cyp1a1 oral cavity cancer Cyp1a1 oral squamous cell carcinoma Cyp1a1 osteosarcoma Cyp3a2 ovarian cancer Ugt1a1 ovarian carcinoma Cyp3a2 Parkinson's disease Cyp1a1 Parkinsonism Cyp1a1 peptic ulcer disease Cyp2c6 periodontitis Cyp1a1 peripheral nervous system disease Cyp2c79 peripheral vascular disease Cyp1a1 Phenacetin O-Deethylase, Deficiency of Cyp1a2 Plasmodium falciparum malaria Cyp2c6 pneumonia Cyp1a1 polycystic ovary syndrome Cyp1a1 Polyuria Ugt1a1 Poor Drug Metabolism, CYP2C19-Related Cyp2c6 Poor Metabolism of Proguanil Cyp2c6 porphyria cutanea tarda Cyp1a1 , Cyp1a2 Prenatal Exposure Delayed Effects Cyp1a1 primary ovarian insufficiency Cyp2c6 prostate cancer Cyp1a1 Prostatic Neoplasms Cyp1a1 , Cyp2c11 , Cyp2c6 , Cyp3a2 psoriasis Cyp1a1 psoriatic arthritis Cyp1a1 pulmonary hypertension Cyp1a1 Pulmonary Hypertension, Hypoxia-Induced Cyp1a1 reactive arthritis Cyp1a1 renal cell carcinoma Cyp1a1 renal hypertension Cyp2c79 Rhabdomyolysis Cyp2c79 Rhabdomyolysis, Cerivastatin-Induced Cyp2c79 Sepsis Cyp1a1 , Cyp1a2 sickle cell anemia Cyp2c6 Sinus Tachycardia Cyp1a1 Sjogren's syndrome Cyp1a1 small cell carcinoma Ugt1a1 splenic disease Cyp1a2 Splenomegaly Cyp1a2 Spontaneous Abortions Cyp1a1 squamous cell carcinoma Cyp1a2 Starvation Ugt1a1 stomach cancer Cyp1a1 Subarachnoid Hemorrhage Cyp3a2 systemic lupus erythematosus Cyp1a1 Tardive Dyskinesia Cyp1a2 thrombosis Cyp2c6 Torsades de Pointes Cyp3a2 tuberculosis Cyp2c6 type 1 diabetes mellitus Ugt1a1 type 2 diabetes mellitus Cyp1a1 , Cyp1a2 , Cyp2c6 , Cyp3a2 , Ugt1a1 urinary bladder cancer Cyp1a1 , Cyp2c11 Ventricular Remodeling Cyp1a1 Vitamin A Deficiency Cyp2c11 VITAMIN D-DEPENDENT RICKETS, TYPE 3 Cyp3a2 Vitamin E Deficiency Cyp1a2
