Ontogeny Of In Vivo Cyp3a4 Activity In The First Months Of Life

Introduction: Document maturational changes of in vivo CYP3A4 activity in the first months of life.

Methods: The contribution of tramadol (M), O-demethyl (M1, CYP2D6 mediated) tramadol and N-demethyl tramadol (M2, CYP3A4 mediated) to overall tramadol elimination and the log M/M2 were assessed in 24 hours urine collections during continuous intravenous tramadol administration and correlations with perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] were investigated (1).

Results: Of the total amount of M administered in a 24 hours interval, 34.5 (SD 6.1)% was retrieved in the urine as parent compound or metabolite in the first 24 hours in 25 neonates and young infants (PMA 25–53 weeks). This retrieval primarily consisted of M 79 (SD 18)%, M1 contributed 10 (SD 17)% and M2 3 (SD 3.4)%. Correlations of the contribution of M (r=–0.73), M1 (r=0.68) and M2 (r=0.4) to overall M elimination with increasing PMA were observed. Mean log M/M2 was 1.44 (SD 0.46). An inverse correlation between log M/M2 ratio and PMA (r=–0.66) and PNA (r=–0.5) was observed with a maturational half life of the log M/M2 ratio of 16 to 20 weeks. In a multiple regression model, PMA remained the only significant variable to explain interindividual log M/M2 variability.

Conclusions: PMA is the most important variable observed in the maturational changes of in vivo CYP3A4 activity with a maturational half life of the log M/M2 of 16 to 20 weeks. Compared to earlier reported developmental changes in CYP2D6 activity, changes in CYP3A4 activity are relatively delayed in the first months of life.

(1) Allegaert et al. Eur J Clin Pharmacol 2005;61:837–842