Site-dependent intestinal hydrolysis of valproate and morphine glucuronide in the developing rat

A previous pharmacokinetic study in developing rats suggested that enterohepatic recirculation of valproic acid was absent prior to weaning. One explanation for this observation is that the rate, extent, and/or primary site of glucuronide hydrolysis in the gastrointestinal tract changes during postnatal development. To test this hypothesis, the hydrolysis of two model glucuronide conjugates, valproate glucuronide and morphine-3-β,D- glucuronide, was examined in vitro in homogenates of small and large intestine obtained from rats at 5-60 days postpartum. Analysis of initial hydrolysis rates indicated that the principal hydrolytic site for both glucuronide conjugates shifted from the upper to lower intestine as the animals developed. The initial hydrolysis rate (nmol/min/g) for valproate glucuronide decreased from 38.1 ± 10.2 to 8.25 ± 2.42 in the small intestine, and increased from 14.2 ± 2.3 to 105 ± 22 in the large intestine, as rats developed from 5 to 60 days postpartum, respectively. Likewise, the intestinal hydrolysis rate for morphine-3-β,D-glucuronide decreased from 3.70 ± 0.46 to 0.646 ± 0.165 in the small intestine, and increased from 3.50 ± 0.48 to 115 ± 30 in the large intestine, as rats developed from 5 to 60 days postpartum, respectively. If hydrolysis occurs immediately after excretion of conjugate into the intestine in neonatal rats, minimal temporal delay between excretion of conjugate and reabsorption of liberated parent may occur, therefore concealing the secondary increase in serum drug concentrations associated with enterohepatic recirculation. In contrast, the time required for conjugates to reach the primary hydrolytic site in adult animals is sufficient for appearance of secondary peaks in the serum drug concentration-time profile.