Postmenstrual age and CYP2D6 polymorphisms determine urinary tramadol O-demethylation excretion in critically ill neonates and infants

Introduction

Interindividual variability in drug metabolism is based on constitutional, environmental and genetic factors but mainly reflects ontogeny in early neonatal life. We therefore wanted to document determinants of O-demethylation activity in critically ill neonates and young infants.

Methods

Tramadol (M) and O-demethyltramadol (M1) concentrations were determined in 24-hour urine collections in neonates in whom continuous intravenous tramadol was administered [1]. Samples were analysed by a HPLC methodology described earlier [2]. The log M/M1 in 24-hour urine collections was calculated and correlations with clinical characteristics and CYP2D6 polymorphisms were investigated.

Results

Based on 86 urine collections, a significant correlation between urine log M/M1 (0.98, SD 0.66) and postmenstrual age (PMA) (r = -0.69) was observed. One-way analysis of variance documented a significant decrease in log M/M1 with an increasing number of active CYP2D6 alleles. In a forward multiple regression model, PMA and the number of active CYP2D6 alleles remained independent determinants of the urine log M/M1.

Conclusion

Both ontogeny (PMA) and CYP2D6 polymorphisms already contribute to the interindividual variability of phenotypic O-demethylation activity of tramadol in critically ill (pre)term neonates and young infants. The current observations are of pharmacodynamic relevance. In addition, we hereby are the first to illustrate the simultaneous impact of both age and genetic polymorphisms on drug metabolism in early life.