AGE-DEPENDENT INTESTINAL-ABSORPTION OF VALPROIC ACID IN THE RAT

The absorption of valproic acid (VPA) across isolated perfused segments of jejunum, ileum and colon was examined in situ in 14-day- to 24-month-old Fischer-344 rats. Within each age group, the intrinsic absorptive clearance (Cl-a) of VPA at a perfusate concentration of 1 mg/ml was highest in the jejunum, lowest in the colon, and intermediate in the ileum. When intestinal Cl-a was normalized for the dry weight of the segment, within-group variability decreased. In all segments, VPA Cl-a normalized by dry weight decreased during development (less than or equal to 20 to 90 days) and remained relatively constant during aging (90 days to 24 months). The mechanism of valproate absorption (active vs. passive) was examined across age in everted intestinal sacs prepared from each of the three segments. Data were consistent with active transport of VPA in the jejunum and ileum of rats of all ages, and in the colon of pre-weanling animals. Colonic absorption of VPA appeared to occur by passive diffusion in adult rats. In contrast, colonic absorption of d-glucose occurred only by passive diffusion in all age groups. These data indicate that, during development, significant alterations in the rate of VPA absorption occur throughout the rat intestine. Furthermore, while active transport of VPA by the small intestine was present throughout the age range investigated, active transport by the colon became negligible by the time of weaning.