Genetic and Nongenetic Factors Influencing Pharmacokinetics of B-Type Natriuretic Peptide

- Study of 95 patients with heart failure receiving human recombinant B-type natriuretic peptide (BNP; nesiritide) infusion and measuring BNP elimination.
- BNP clearance varied greatly across the cohort.
- Heart failure type (ie, preserved vs reduced ejection fraction) correlated with BNP clearance rates.
- Genetic variation in MME and NPR3 may affect BNP clearance rates; this needs replication.

BackgroundNatriuretic 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.MethodsChronic 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.ResultsParticipants' 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).ConclusionsThe pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.