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Research ArticleArticle

Dose-Dependent Pharmacokinetics and Metabolism of Valproic Acid in Newborn Lambs and Adult Sheep

Harvey Wong, Dan W. Rurak, Sanjeev Kumar, Eddie Kwan, Frank S. Abbott and K. Wayne Riggs
Drug Metabolism and Disposition May 2001, 29 (5) 664-675;
Harvey Wong
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Dan W. Rurak
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Sanjeev Kumar
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Eddie Kwan
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Frank S. Abbott
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K. Wayne Riggs
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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

  • 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

  • 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 0–∞u
    AUC0–∞ of unbound drug
    Cb
    protein bound drug concentration
    CLint
    intrinsic clearance
    CLtb
    total body clearance of the total drug
    CL tbu
    total body clearance based upon unbound drug concentrations
    Cu
    unbound drug concentration
    Cmidu
    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 ssu
    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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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Dose-Dependent Pharmacokinetics and Metabolism of Valproic Acid in Newborn Lambs and Adult Sheep

Harvey Wong, Dan W. Rurak, Sanjeev Kumar, Eddie Kwan, Frank S. Abbott and K. Wayne Riggs
Drug Metabolism and Disposition May 1, 2001, 29 (5) 664-675;

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Research ArticleArticle

Dose-Dependent Pharmacokinetics and Metabolism of Valproic Acid in Newborn Lambs and Adult Sheep

Harvey Wong, Dan W. Rurak, Sanjeev Kumar, Eddie Kwan, Frank S. Abbott and K. Wayne Riggs
Drug Metabolism and Disposition May 1, 2001, 29 (5) 664-675;
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