Surge in Expression of Carboxylesterase 1 During the Post-neonatal Stage Enables a Rapid Gain of the Capacity to Activate the Anti-influenza Prodrug Oseltamivir

Carboxylesterases constitute a large class of hydrolytic enzymes [1, 2]. These enzymes are major pharmacokinetic determinants of ester/amide dugs and detoxify against many insecticides [1–3]. In addition, these enzymes hydrolyze endogenous lipids and are involved in the assembling of lipoproteins [4, 5]. Carboxylesterases exhibit overlapping substrate specificity; however, many drugs are hydrolyzed predominately by a single carboxylesterase [1, 2, 6]. Although there are exceptions, the relative sizes between the alcohol and acyl (acid) moieties of an ester contribute significantly to the isoform-specific hydrolysis. For example, the anticancer prodrug irinotecan has a larger alcohol moiety and is hydrolyzed primarily by carboxylesterase 2 (CES2) [7]. In contrast, the anti-influenza prodrug oseltamivir has a larger acid group and is hydrolyzed by carboxylesterase 1 (CES1) [8]. The recent influenza pandemic led to the wide use of oseltamivir among patients of all age groups [9, 10]. Initial reports showed that infants and children, even those only months old, produced sufficient levels of the hydrolytic metabolite [11, 12]. A previous study from this laboratory has shown that fetal livers had only ∼5% of the adult CES1 capacity, depending on the experimental parameters (messenger RNA [mRNA], protein, or hydrolysis levels) [13]. The present study was performed to test the hypothesis that a surge in expression of CES1 during the early developmental period enables a rapid gain of oseltamivir activation capacity. To test this hypothesis, liver tissues from donors at birth to age ∼6 months were collected and analyzed for the activation of oseltamivir and the expression of CES1.