In Vivo Glucuronidation Activity of Drugs in Neonates: Extensive Interindividual Variability Despite Their Young Age

Abstract

Compared with phase I isoenzymes, data on isoenzyme-specific phenotypic activity of uridine diphosphate glucuronosyltransferase (UGT) and its covariates in neonates are limited. In vivo observations on morphine, paracetamol (acetaminophen), and propofol disposition throughout childhood confirm the overall low-glucuronidation activity in neonates observed in in vitro studies. In addition to the phenotypic low-glucuronidation activity, in vivo observations of bilirubin (UGT1A1), morphine (UGT2B7), paracetamol (UGT1A6), and propofol (UGT1A9) glucuronidation in neonates display extensive interindividual variability, only in part explained by postmenstrual and postnatal age. Covariates like disease state characteristics (decreased morphine metabolism during therapeutic head cooling), genetic polymorphisms (UGT1A1 genetic variants and differences in bilirubin metabolism), or environmental factors (increased urinary excretion of paracetamol-glucuronide by repeated administration of paracetamol) further contribute to this variability. A focused approach to unveil covariates of the interindividual range is needed to improve our knowledge on drug disposition in early life.

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

“…Activity remains low in the first 10 days of post-natal life and then begins to increase in both term and preterm babies [50]. Again co-morbidities, surgery and gene polymorphisms can affect this pattern of development [45]. The capacity of morphine metabolism by UGT2B7 is closely related to body weight as opposed to surface area and post-natal age after the first 10 days of life.…”

“…Factors affecting the development of this pathway include post-natal and post-menstrual age, other medications, genetic polymorphisms, co-morbidities and maternal smoking status [45]. Phenobarbitone administration has been reported to induce UGT1A1 activity [49].…”

“…Phase II reactions include glucuronidation, sulphation, methylation and acetylation and so are an important part of drug metabolism and the biotransformation of endogenous compounds including steroids and bilirubin. The largest group of enzymes involved in these reactions are uridine diphosphate glucuronosyltransferase (UDP) isoenzymes [45]. The development of UDP-glucuronosyltransferase (UGT) has both pharmacokinetic (as in chloramphenicol toxicity) and pharmacodynamic (as part of morphine glucuronidation) importance to newborn care [7].…”

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

“…In vitro, Strassburg et al demonstrated that children had lower hepatic glucuronidation activities than adults [23]. In vivo, low glucuronidation activities in children were characterized for morphine (UGT2B7), paracetamol (UGT1A6) and propofol (UGT1A9) [27]. The identification of the responsible UGT isoforms and genotype-phenotype studies should be evaluated in further research.…”

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

“…In the case of lack of change in the acetaminophen/acetaminophen glucuronide phenotyping index, the investigator will have relevant information on the UGT1A pool, as previously studied using acetaminophen as a probe (Volak et al 2013). In the case that there is a change, additional investigations could be performed using more specific probes such as endogenous bilirubin (UGT1A1) or propofol (UGT1A9) as already reported in neonates (Allegaert et al 2009). …”