Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Abstract

ABSTRACT:To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eightysix 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r ϭ Ϫ0.69 and Ϫ0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (F value 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R 2 0.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivo ontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population. I nterindividual variability in drug metabolism is based on constitution, environment, and genetics, but mainly reflects ontogeny in early life. Although the total cytochrome (CYP) content in fetal liver is 30 to 60% of adult content, iso-enzyme specific ontogeny precludes generalization of a single developmental pattern, necessitating iso-enzyme specific assessment (1). Based on observations on in vivo dextrometorphan in healthy infants and tramadol metabolism in critically ill (pre)term neonates and young infants, phenotypic activity of N-demethylation (CYP3A) displays slower increase to adult activity compared with O-demethylation (CYP2D6) (2,3). In addition to ontogeny, co-morbidity, co-medication, or polymorphisms in drug metabolizing enzymes and transporters likely further contribute to the interindividual variability of drug disposition (1,4,5).Tramadol (M) hydrochloride is a 4-phenyl-piperidine analogue of codeine and is a racemic mixture of two enantiomers. O-demethylation of (ϩ)-tramadol to O-(ϩ)-demethyl tramadol (M1) is catalyzed by CYP2D6 and to a much lesser extent, by CYP2B6. Tramadol therefore provide us with a probe drug to assess phenotypic variability in O-demethylation activity. The logarithmic value of tramadol over O-demethyl tramadol (log M/M1) has been used to study in vivo CYP2D6 activity in adults, children, and neonates (6 -9). Based on urine log M/M1 values, the impact of postmenstrual age (PMA) on phenotypic O-demethylation activity in 29 neonates and young infants was described, but PMA only in part explained (R adj Ϫ0.51) the interindividual variability in O-demethylation activity (8). The purpose of this study was to estimate the impact of ontogeny [PMA, postnatal age (PNA), weight] and pharmacogenetics (quantified by the CYP2D6 activity score) on interindividual variability of O-demethylation in earl...

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“…CYP2D6 is subject to genetic differences in activity levels. Toxicities from drugs metabolized via this pathway can be related to development of the pathway along with genetic predisposition to being a poor or ultra-rapid metabolizer [32]. The poor metabolizer genotype has been thought to be in part responsible for toxicities shown following perinatal exposure to paroxetine [39].…”

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“…However, a single case observation does not represent the interindividual variability in clinical symptoms. We therefore felt it appropriate to draw the attention of the reader to recently reported observations on the interindividual variability in the pharmacokinetics and pharmacodynamics of moderately potent opioids such as tramadol and codeine in perinatal life [2][3][4][5][6].…”

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