Urinary metabolites to assess in vivo ontogeny of hepatic drug metabolism in early neonatal life

In addition to size-dependent allometric metabolic activity, most isoenzymes display age-dependent isoenzyme-specific outogeny. We therefore need probe drugs to describe isoenzyme-specific outogeny to develop more sophisticated, physiologically based models. we illustrate the feasibility and the relevance of in vivo assesment of hepatic metabolism, based on observations on urinary elimination of paracetamol and tramadol metabolites in neonates. On the basis of the observations on tramadol disposition, we were able to document that O-demethylation phenotypic activity developed soooner when compared with N-demethylation. During repeated administration of intravenous paracetamol, it was documented that in addition to postmenstrual and postnatal age (PNA), repeated administration also contributed to the urinary excretion of glucuronidated paracetamol. In both prob drugs evaluated, age only in part explained the interindividual variability observed. Urine metabolites to assess in vivo metabolism of drugs routinely administered in neonates likely increase both the feasibility and clinical relevance of studies on in vivo isoenzyme-specific ontogeny in neonates. (C) 2007 Prous Science. All rights reserved.