Assessment of tear concentrations on therapeutic drug monitoring. II. Pharmacokinetic analysis of valproic acid in guinea pig serum, cerebrospinal fluid, and tears.
OBJECTIVE
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 (KINCSF and KOUTCSF). [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 = KINCSF/KOUTCSF x [Cf], [Cf] = KOUT/KINT x [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.
Sato
S
S
Department of Pharmaceutics, Niigata College of Pharmacy, Japan. sato@niigata-pharm.ac.jp
Kitagawa
S
S
Nakajima
M
M
Shimada
K
K
Honda
A
A
Miyazaki
H
H
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods*; D006168:Guinea Pigs; D008297:Male; D013666:Tears / Q000378:metabolism*; D014635:Valproic Acid / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D014635:Valproic Acid