Maja Matic1, Saskia N de Wildt, Laure Elens, Jan N de Hoon, Pieter Annaert, Dick Tibboel, Ron H N van Schaik, Karel Allegaert. 1. *Department of Clinical Chemistry, Erasmus University Medical Centre; Departments of †Intensive Care and ‡Paediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, the Netherlands; §Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels; ¶Center for Clinical Pharmacology, University Hospitals Leuven & Department of Pharmaceutical and Pharmacological Sciences, University Hospitals; ‖Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven; and **Neonatal Intensive Care Unit, University Hospitals, Leuven, Belgium.
Abstract
BACKGROUND: This study determined whether the SLC22A1 [encoding the organic cation transporter 1 (OCT1)] genotype could explain, in addition to the postmenstrual age (referring to gestational plus postnatal age) and CYP2D6 genotype, the tramadol (M) pharmacokinetic variability in early infancy. METHODS: Fifty infants, median postmenstrual age 39.5 (interquartile range: 36.8-41.3) weeks, received an i.v. M loading dose (2 mg/kg) followed by a continuous infusion (5-8 mg·kg·24 h). Blood was sampled from 4 to 24 hours after start of the M treatment, which generated 230 observations. M and O-desmethyltramadol (M1) concentrations were measured by high-performance liquid chromatography. RESULTS: Linear mixed-model analysis illustrated that the SLC22A1/OCT1 genotype was independently associated with a log-transformed M1/M ratio (P = 0.013), with carriers of <2 SLC22A1/OCT1 functional gene copies having a higher M1/M ratio (2.25; 95% CI, 2.01-2.48) than infants with 2 functional gene copies (1.86; 95% CI, 1.66-2.06). The CYP2D6/SLC22A1 combined genotype was associated with 57.8% higher M1/M ratio in carriers of ≥2 CYP2D6 functional gene copies and <2 SLC22A1/OCT1 functional gene copies compared with infants with <2 active CYP2D6 functional gene copies and SLC22A1/OCT1 normal activity (P < 0.001). CONCLUSIONS: These findings highlight the additional role of SLC22A1/OCT1 genetics in M1 exposure in neonates. They also suggest that OCT1 is already active early after birth, which may have impact on the disposition of other OCT1 substrates in this population.
BACKGROUND: This study determined whether the SLC22A1 [encoding the organic cation transporter 1 (OCT1)] genotype could explain, in addition to the postmenstrual age (referring to gestational plus postnatal age) and CYP2D6 genotype, the tramadol (M) pharmacokinetic variability in early infancy. METHODS: Fifty infants, median postmenstrual age 39.5 (interquartile range: 36.8-41.3) weeks, received an i.v. M loading dose (2 mg/kg) followed by a continuous infusion (5-8 mg·kg·24 h). Blood was sampled from 4 to 24 hours after start of the M treatment, which generated 230 observations. M and O-desmethyltramadol (M1) concentrations were measured by high-performance liquid chromatography. RESULTS: Linear mixed-model analysis illustrated that the SLC22A1/OCT1 genotype was independently associated with a log-transformed M1/M ratio (P = 0.013), with carriers of <2 SLC22A1/OCT1 functional gene copies having a higher M1/M ratio (2.25; 95% CI, 2.01-2.48) than infants with 2 functional gene copies (1.86; 95% CI, 1.66-2.06). The CYP2D6/SLC22A1 combined genotype was associated with 57.8% higher M1/M ratio in carriers of ≥2 CYP2D6 functional gene copies and <2 SLC22A1/OCT1 functional gene copies compared with infants with <2 active CYP2D6 functional gene copies and SLC22A1/OCT1 normal activity (P < 0.001). CONCLUSIONS: These findings highlight the additional role of SLC22A1/OCT1 genetics in M1 exposure in neonates. They also suggest that OCT1 is already active early after birth, which may have impact on the disposition of other OCT1 substrates in this population.
Authors: Sarinj Fattah; Abhijit Babaji Shinde; Maja Matic; Myriam Baes; Ron H N van Schaik; Karel Allegaert; Celine Parmentier; Lysiane Richert; Patrick Augustijns; Pieter Annaert Journal: Pharm Res Date: 2017-03-31 Impact factor: 4.200