BACKGROUND AND OBJECTIVE: Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.
BACKGROUND AND OBJECTIVE:Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.
Authors: M V Tzvetkov; S V Vormfelde; D Balen; I Meineke; T Schmidt; D Sehrt; I Sabolić; H Koepsell; J Brockmöller Journal: Clin Pharmacol Ther Date: 2009-06-17 Impact factor: 6.875
Authors: Laura M Hodges; Svetlana M Markova; Leslie W Chinn; Jason M Gow; Deanna L Kroetz; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-03 Impact factor: 2.089
Authors: Maya K Leabman; Conrad C Huang; Michiko Kawamoto; Susan J Johns; Douglas Stryke; Thomas E Ferrin; Joseph DeYoung; Travis Taylor; Andrew G Clark; Ira Herskowitz; Kathleen M Giacomini Journal: Pharmacogenetics Date: 2002-07
Authors: A E Busch; U Karbach; D Miska; V Gorboulev; A Akhoundova; C Volk; P Arndt; J C Ulzheimer; M S Sonders; C Baumann; S Waldegger; F Lang; H Koepsell Journal: Mol Pharmacol Date: 1998-08 Impact factor: 4.436
Authors: María C Ovejero-Benito; Dolores Ochoa; Teresa Enrique-Benedito; Miriam Del Peso-Casado; Pablo Zubiaur; Marcos Navares; Manuel Román; Francisco Abad-Santos Journal: J Pers Med Date: 2022-05-13