Both postnatal and postmenstrual age contribute to the interindividual variability in tramadol glucuronidation in neonates

Abstract: Introduction: Although of pharmacokinetic and -dynamic relevance, data on ontogeny of UDP-glucuronosyltransferase (UGT) activity in neonates are scant. We therefore wanted to assess the impact of both postnatal and postmenstrual age (PNA/PMA) on the interindividual variability of glucuronidation to overall tramadol urinary elimination in neonates. Methods: O-demethyl tramadol (M1) and M1-glucuronide (M1G) were determined in 24 hour urine collections during continuous intravenous tramadol administration in neonates. Glucuronidation fraction (%) was calculated by the ratio of M1G to the sum of M1G and M1 free (M1total). Fractions (%) in early (<day 8) or late neonatal life (day 8–28) were compared (Mann–Whitney U) and forward multiple regression was applied to assess the impact of various covariates. Results: Urine collections were available in 59 neonates with a PNA of 6 (1–28) days and a PMA of 38 (SD 4) weeks. Mean M1G/M1total was 27 (SD 15) % and was significantly lower in early compared to late neonatal life (22 versus 32%, p =0.0001). In a forward multiple regression model, both PMA and early versus late neonatal life remained independent variables to explain the interindividual variability in M1G/M1total. Conclusions: Besides PMA, there is an additional, independent impact of PNA since phenotypic glucuronidation activity is significantly lower in the first week of postnatal life. These findings should be taken into account in the assessment of compounds for whom glucuronidation is of pharmacokinetic, pharmacodynamic or toxicological relevance. [Copyright &y& Elsevier]