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Abstract: TH-PO357

Characterization of Metoprolol and Metabolite Concentrations Pre and Post Hemodialysis: Potential Implications for Intradialytic Hypotension and Post-Dialysis Fatigue

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Dean, Michael C., University of Michigan, Ann Arbor, Michigan, United States
  • Costello, Gabrielle M., University of Michigan, Ann Arbor, Michigan, United States
  • Souza, Ernane, University of Michigan, Ann Arbor, Michigan, United States
  • Felton, Jeremy Antonio, University of Michigan, Ann Arbor, Michigan, United States
  • Szamosfalvi, Balazs, University of Michigan, Ann Arbor, Michigan, United States
  • Pai, Manjunath P., University of Michigan, Ann Arbor, Michigan, United States
  • Pai, Amy Barton, University of Michigan, Ann Arbor, Michigan, United States
Background

Previous pharmacokinetic (PK) studies of metoprolol succinate (MPL) were conducted before high-flux HD and did not evaluate post-HD rebound or parent:metabolite (P:M) ratios. Intercompartmental redistribution of antihypertensives may contribute to intradialytic hypotension and post-dialysis fatigue. The aim of this study was to characterize the PK of MPL and α-hydroxymetoprolol during and post-HD.

Methods

Eligible patients were >18 years, on HD 3 days a week for 3.5-5 hours (h), daily dose of MPL 25-200mg, and hemoglobin >9.5 g/dL. Arterio-venous (AV) paired samples were collected prior to HD initiation, 0.5h, 2h, and end of treatment. Post-HD sampling occurred at 0.5, 2, and 4h. Serum samples were assayed by liquid chromatography-tandem mass spectrometry and a non-parametric population PK model was used (PMetricsTM LAPK). T0 samples were analyzed for CYP2D6*4.

Results

Eight patients (5 male, 3 female; Age 59±17 years) were enrolled. The MPL PK data were best fit with a linear, 2-compartment model with absorption rate and fraction absorbed fixed to known values from literature. The model predicted MPL clearance (CL) was relatively unchanged on- and post-HD with a mean (CV) of 46.5 (17.4%) and 41.9 (54.4%) L/h, respectively. AV-dialytic CL was minimal (13.1±8.8% of total CL). The mean volume of distribution (Vd) in central compartment (Vc) decreased: 119.7 (103.2%) L on-HD to 18.4 (128.7%) L post-HD. Mean peripheral compartment Vd (Vp) increased: 17.7 (252.2%) L on-HD to 160.0 (0.0%) L post-HD. Vd changes resulted in significant MPL flux from Vp to Vc on-HD driven by redistribution and from Vc to Vp post-HD due to hemoconcentration. Higher MPL concentrations were seen at 2h on-HD and 4h post-HD. The P:M ratios were variable suggesting phenotypic differences in CYP2D6 activity. Three CYP2D6*4 heterozygotes were identified, but only one showed decreased metabolism based on P:M ratio.

Conclusion

Large changes in Vd due to ultrafiltration drive fluctuating MPL concentrations during and after HD, resulting in highly variable MPL serum concentrations. This may contribute to intradialytic hypotension and/or post-dialysis fatigue. Dialytic CL does not appear to contribute significantly to varying MPL concentration profiles.