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ARTICLES: Jeffrey C. Stevens, Sandra A. Marsh, Matthew J. Zaya, Karen J. Regina, Karthika Divakaran, Min Le, and Ronald N. Hines Developmental Changes in Human Liver CYP2D6 Expression Drug Metab Dispos 2008; 36: 1587-1593 [Abstract] [Full text] [PDF]

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Developmental changes in CYP2D6 expression in early life: an in vivo approach to assess co-variates

Karel Allegaert, Brian J. Anderson and John N. van den Anker   (5 June 2008)

Developmental changes in CYP2D6 expression in early life: an in vivo approach to assess co-variates 5 June 2008
Karel Allegaert University Hospital Gasthuisberg, Brian J. Anderson and John N. van den Anker Send letter to journal: Re: Developmental changes in CYP2D6 expression in early life: an in vivo approach to assess co-variates karel.allegaert{at}uz.kuleuven.ac.be Karel Allegaert, et al.	Dear editor, We read with great interest the paper of Stevens et al. on developmental changes in human liver CYP2D6 expression. Based on the assessment of in vitro dextromethorphan O-demethylase activity in a set of 222 pediatric liver samples, the authors documented that both age and genetics (CYP2D6 polymorphisms) were determinants of CYP2D6 dependent drug metabolism (Stevens et al, 2008). We fully agree with the authors that a similar in vivo assessment is in part hampered by ethical and logistical concerns. However, in vivo iso-enzyme specific assessment based on probe drugs administered during routine clinical care in early life in combination with multivariable models like non-linear mixed effects (NONMEM) models provide us with the tools to simultaneously disentangle the impact of various co-variables (size, age, environment, co-morbidity and polymorphisms) (Anderson et al, 2007). Shortly before submission of the work of Stevens et al, we reported on the determinants of tramadol clearance in early life using an NONMEM approach. Tramadol also undergoes CYP2D6 mediated O-demethylation and has been suggested as an alternative probe drug to assess phenotypic CYP2D6 activity (Pedersen et al, 2005). In a group of 57 preterm and term neonates to whom continuous intravenous tramadol was administered for clinical indications, it was documented that both postmenstrual age (PMA, i.e. gestational age at birth + postnatal age, in weeks) and CYP2D6 polymorphisms (CYP2D6 activity score) predicted to a large extent O- demethyl tramadol formation clearance without additional impact of co- morbidity (cardiopathy, cardiac surgery) or postnatal age. In preterm neonates (< 37 weeks PMA), phenotypic CYP2D6 activity was low, independent of the CYP2D6 activity score with a subsequent PMA-dependent progressive increase in the contribution of the CYP2D6 activity score to the interindividual variability in phenotypic CYP2D6 activity observed (Allegaert et al, 2008a). This complex and PMA-dependent impact of the CYP2D6 activity score on phenotypic CYP2D6 activity was confirmed in 24 h urine collections in a more extended cohort of 86 of (pre)term neonates and young infants. These in vivo observations are in agreement with similar observations on dextromethorphan metabolism based on urine sampling in healthy term neonates from 42 weeks PMA onwards with subsequent repeated sampling in the first year of life since CYP2D6 ontogeny mainly seems to evolve before term age (Allegaert et al, 2008b; Blake et al, 2007). In conclusion, the in vivo observations on tramadol metabolism confirm the in vitro dextromethorphan findings described by Stevens et al. on the impact of age and CYP2D6 polymorphisms. In addition, based on the in vivo tramadol model, it was documented that there is no additional impact of postnatal age or cardiopathy/cardiac surgery once postmenstrual age and CYP2D6 activity score has been taking into account. A combined approach to assess developmental changes in drug disposition based on both in vitro and in vivo models should provide all stakeholders involved (academia, patients and their parents, clinicians) with essential information to further improve the clinical use of drugs in children.