PT  - JOURNAL ARTICLE
AU  - Harvey Wong
AU  - Dan W. Rurak
AU  - Sanjeev Kumar
AU  - Eddie Kwan
AU  - Frank S. Abbott
AU  - K. Wayne Riggs
TI  - Dose-Dependent Pharmacokinetics and Metabolism of Valproic Acid in Newborn Lambs and Adult Sheep
DP  - 2001 May 01
TA  - Drug Metabolism and Disposition
PG  - 664--675
VI  - 29
IP  - 5
4099  - http://dmd.aspetjournals.org/content/29/5/664.short
4100  - http://dmd.aspetjournals.org/content/29/5/664.full
SO  - Drug Metab Dispos2001 May 01; 29
AB  - 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