TY - JOUR T1 - Dose-Dependent Pharmacokinetics and Metabolism of Valproic Acid in Newborn Lambs and Adult Sheep JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 664 LP - 675 VL - 29 IS - 5 AU - Harvey Wong AU - Dan W. Rurak AU - Sanjeev Kumar AU - Eddie Kwan AU - Frank S. Abbott AU - K. Wayne Riggs Y1 - 2001/05/01 UR - http://dmd.aspetjournals.org/content/29/5/664.abstract N2 - Dose-dependent pharmacokinetics and metabolism of valproic acid (VPA) were studied in newborn and adult sheep to assess age-related differences in plasma protein binding and metabolic elimination. Newborn lambs received either a 10- (n = 8), 50- (n = 5), 100- (n = 4), or 250-mg/kg (n = 4) VPA i.v. bolus. Individual adult sheep (n = 5) received all four doses in a random order with an appropriate washout period between experiments. Unbound or metabolic clearance of VPA was significantly higher in adult sheep at the two lower doses when compared with lambs, and similar to the lambs at the two higher doses. Plasma protein binding was nonlinear at all doses. Estimates of binding capacity (Bmax1) at the saturable site were higher in adults (91.8 μg/ml) when compared with lambs (44.9 μg/ml), whereas the opposite trend was observed for binding affinity [Kd1 = 9.6 μg/ml (adult) versus 3.2 μg/ml (lambs)]. Characterization of developmental differences in overall VPA metabolic elimination involved fitting of unbound VPA plasma concentration data to a two-compartment model with Michaelis-Menten elimination. This resulted in similar in vivo estimates of apparent Vmax [445.0 μg/min/kg (adult) versus 429.9 μg/min/kg (lambs)]. However, apparent Km estimates appeared to be higher in lambs [30.0 μg/ml (adult) versus 69.6 μg/ml (lambs)]. Similar findings were obtained from in vivo estimates ofVmax and Km for VPA glucuronidation obtained from VPA-glucuronide metabolite urinary excretion data. Thus, it appears that age-related differences in metabolic clearance may be related to differences in the apparent in vivo Km as opposed toVmax of VPA glucuronidation. The American Society for Pharmacology and Experimental Therapeutics ER -