Analysis of tissue distribution of valproate in guinea-pigs: evidence for its capacity-limited tissue distribution.

The tissue distribution of valproic acid (VPA) was investigated over a wide range of steady-state plasma levels (Css) in guinea-pigs. The VPA concentrations in various tissues, except the kidney, were all lower than in plasma. Tissue-to-unbound plasma concentration ratios (Kpu) of VPA for adipose, heart, kidney, liver, lung, muscle, pancreas and skin all decreased significantly with increasing unbound plasma concentration (Cuss). The Kpu for brain (0.5-0.9), intestine, spleen and stomach failed to show significant change with Cuss. The disposition of VPA in tissues is adequately described by a model in which VPA was distributed in interstitial and intracellular fluid and bound to interstitial albumin, with limited tissue binding. Tissue binding was extensive only in the kidney. Most of the measured apparent Kpu values agreed well with simulated Kpu values. Steady-state tissue concentration of VPA can be predicted from Css and Cuss when reference data for interstitial albumin and tissue total water are available.