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Developmental pharmacology, pharmacogenomic variability and anaesthesia
- Karel Allegaert (4 June 2009)
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Karel Allegaert, MD, PhD, consultant NICU
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Dear editor, We read the review paper on pharmacogenomic variability and anaesthesia by Searle and Hopkins with great interest. The promise of pharmacogenomics (PGx), i.e. the study of the role of inheritance in the individual variation in drug response lies in its potential to further identify the right drug and dosing regimen in every individual patient. Observations on the impact of cytochrome P450 (CYP) 2D6, the µ-opioid receptor µ 1 (OPRM1), UDP-glucuronosyl (UGT) 2B7 isoenzyme, efflux transporter P- glycoprotein (P-gp) and ATP-binding cassette B1 (ABCB1/multiple drug resistence 1 (MDR1) polymorphisms on opioid disposition were discussed to illustrate the potential impact of PGx on pain management [3]. PGx are – however – only one group of co-variates of interindividual variability. People differ and the interindividual phenotypic variability is the final result of maturation, genomic variation and environment. Other clinical characteristics, like ontogeny (i.e. age-dependent maturation), co-morbidity (e.g. hepatic or renal dysfunction) or co- medication should be considered together with the genomic variation. The authors clearly already mention in their abstract that variability to drug response is most likely the final result of a complex interaction of multiple factors [3]. We fully support their conclusions made, but felt it to be appropriated to elaborate on the concept of pharmacogenetic variability and developmental pharmacology based on tramadol observations earlier reported in this journal [2]. Phenotypic variation in drug metabolism is based on constitutional, environmental and genetic factors but in early life, mainly reflects ontogeny, i.e. age dependent phenotypic activity. This is also true for CYP2D6 ontogeny [1,2]. Based on observations collected in neonates and young infants during continuous intravenous tramadol (M) administration, we were able to show that both postmenstrual age and CYP2D6 activity score were independent covariates of the interindividual variability observed. With increasing postmenstrual age, the contribution of the CYP2D6 activity score becomes more relevant [1,2]. Based on these observations, adverse effects after tramadol administration to a neonate are less likely due to M1 formation clearance but more likely due to tramadol accumulation while in late infancy, increased M1 formation in ultrarapid CYP2D6 metabolizers (CYP2D6 activity score > 2) can be observed [1,2]. References: 1.Allegaert K, Van den Anker JN, de Hoon JN, van Schaik RH, Debeer A, Tibboel D, Naulaers G, Anderson BJ. Covariates of tramadol disposition in the first months of life. Br J Anaesth 2008; 100: 525-32. 2.Allegaert K, van Schaik RH, Vermeersch S, Verbesselt R, Cossey V, Vanhole C, van Fessem M, de Hoon J, van den Anker JN. Postmenstrual age and CYP2D6 polymorphisms determine tramadol o-demethylation in critically ill neonates and infants. Pediatr Res 2008; 63:674-9. 3.Searle R, Hospkins PM. Pharmacogenomic variability and anaesthesia. Br J Anaesth 2009; DOI 10.1093/bja/aep130. Conflict of Interest:None declared |
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