Abstract
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.
Footnotes
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Send reprint requests to: Dr. K. W. Riggs, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. E-mail:riggskw{at}interchange.ubc.ca
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These studies were supported by funding from the Medical Research Council of Canada. H.W. was the recipient of a Pharmaceutical Manufacturers Association of Canada/-Health Research Foundation and Medical Research Council Graduate Scholarship in Pharmacy. S.K. was the recipient of a University of British Columbia Graduate Fellowship. D.W.R. is the recipient of an investigatorship award from the British Columbia Children's Hospital Foundation.
- Abbreviations used are::
- VPA
- valproic acid
- AIC
- Akaike's information criterion
- AUC0–∞
- area under the curve of arterial plasma concentration-time profile
- AUC
- AUC0–∞ of unbound drug
- Cb
- protein bound drug concentration
- CLint
- intrinsic clearance
- CLtb
- total body clearance of the total drug
- CL
- total body clearance based upon unbound drug concentrations
- Cu
- unbound drug concentration
- C
- unbound plasma concentration at the midpoint of the urine collection interval
- CV
- coefficient of variation
- fp
- area weighted unbound fraction of the drug
- fu
- unbound fraction
- tmid
- time at the midpoint of the urine collection interval
- Vdss
- steady-state volume of distribution
- Vd
- steady-state volume of distribution based upon unbound drug concentrations
- Vdss′
- steady-state volume of distribution corrected for the effects of saturable protein binding
- 2-ene VPA
- 2-n-propyl-2-pentenoic acid
- 3-ene VPA
- 2-n-propyl-3-pentenoic acid
- 4-ene VPA
- 2-n-propyl-4-pentenoic acid
- 3-keto VPA
- 2-n-propyl-3-oxopentanoic acid
- 4-keto VPA
- 2-n-propyl-4-oxopentanoic acid
- 3-
- 4-, and 5-OH VPA, 3-, 4-, and 5-hydroxy VPA, respectively
- 2-PSA
- 2-propylsuccinic acid
- 2-PGA
- 2-propylglutaric acid
- Received August 18, 2000.
- Accepted January 11, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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