Summary
The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p<0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p<0.01) than in fasting samples (10–50%,p<0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p<0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
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Bowdle, T.A., Patel, I.H., Levy, R.H. et al. The influence of free fatty acids on valproic acid plasma protein binding during fasting in normal humans. Eur J Clin Pharmacol 23, 343–347 (1982). https://doi.org/10.1007/BF00613618
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DOI: https://doi.org/10.1007/BF00613618