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Assessment of Tear Concentrations on Therapeutic Drug Monitoring. II. Pharmacokinetic Analysis of Valproic Acid in Guinea Pig Serum, Cerebrospinal Fluid, and Tears

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Abstract

Purpose. To quantitatively describe the pharmacokinetics of valproic acid (VPA) in guinea pig serum (total [Cf+b] and free [Cf]), cerebrospinal fluid (CSF) [C]CSF and tears [C]T using a simple kinetic model, and to examine whether [Cf] and [C]CSF can be predicted by [C]T using the resulting pharmacokinetic parameters.

Methods. [Cf+b], [Cf], [C]CSF and [C]T were determined after bolus i.v. injection of 10 or 20 mg/kg VPA using GC/ECNCI/MS.

Results. [Cf+b] could be quantitatively described by a two compartment model with linear elimination kinetics. [Cf] was separately analyzed using multi-exponential equations. [C]CSF was analyzed using a simple kinetic model in which the CSF compartment is independently connected with the serum compartment by the apparent diffusion constants (K INCSF and K OUTCSF). [C]T was analyzed using the same simple kinetic model used for [C]CSF. The values of [C]CSF and [Cf] in the steady state can be represented by the following equations; [C]CSF = K INCSF/K OUTCSF × [Cf], [Cf] = K OUTT/K INT × [C]T, and indicating that [Cf] and [C]CSF can be predicted by [C]T using the resulting pharmacokinetic parameters.

Conclusions. The measurement of [C]T which can be collected non-invasively and estimated the pharmacokinetic parameters for [Cf], [C]CSF, and [C]T might be a very useful method for TDM of VPA.

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Authors and Affiliations

  1. Department of Pharmaceutics, Niigata College of Pharmacy, 5-13-2 Kamishinei-cho, Niigata, 950-2081, Japan

    Shinji Sato & Shuji Kitagawa

  2. Department of Analytical Chemistry, Niigata College of Pharmacy, 5-13-2 Kamishinei-cho, Niigata, 950-2081, Japan

    Masaharu Nakajima & Kenji Shimada

  3. Food Research Institute of Niigata Prefecture, 2-25 Shinei-cho Kamo-shi, Niigata, 959-1381, Japan

    Masaharu Nakajima

  4. Miyamoto Hospital, 1247 Koda Azuma-cho, Inashiki, Ibaraki, 300-0605, Japan

    Akira Honda

  5. Department of Drug Metabolism and Disposition, Niigata College of Pharmacy, 5-13-2 Kamishinei-cho, Niigata, 950-2081, Japan

    Hiroshi Miyazaki

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  1. Shinji Sato
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  2. Shuji Kitagawa
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  4. Kenji Shimada
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  6. Hiroshi Miyazaki
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Sato, S., Kitagawa, S., Nakajima, M. et al. Assessment of Tear Concentrations on Therapeutic Drug Monitoring. II. Pharmacokinetic Analysis of Valproic Acid in Guinea Pig Serum, Cerebrospinal Fluid, and Tears. Pharm Res 18, 500–509 (2001). https://doi.org/10.1023/A:1011010528642

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