title: Genetic and nongenetic factors influencing pharmacokinetics of B-type natriuretic peptide.
abstract: BACKGROUND
  Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation.
  
  
  METHODS
  Chronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK.
  
  
  RESULTS
  Participants' mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05).
  
  
  CONCLUSIONS
  The pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan. Electronic address: dlanfea1@hfhs.org.
authors.forename: David E
authors.initials: DE
authors.lastname: Lanfear
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Chow
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Badri
authors.initials: B
authors.lastname: Padhukasahasram
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: David
authors.initials: D
authors.lastname: Langholz
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: L Keoki
authors.initials: LK
authors.lastname: Williams
authors.affiliation: Advanced Heart Failure and Transplant Cardiology, Section, Cardiology Division, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D045283:Natriuretic Agents / Q000493:pharmacokinetics*; D020097:Natriuretic Peptide, Brain / Q000493:pharmacokinetics*; D015260:Neprilysin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013318:Stroke Volume
chemical_list: D045283:Natriuretic Agents; D011994:Recombinant Proteins; D020097:Natriuretic Peptide, Brain; D015260:Neprilysin; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C
keywords: Natriuretic peptide; drug metabolism; genetic polymorphisms; heart failure; pharmacogenetics