Abstract
The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-Δ2-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-Δ2-VPA than with VPA (104–106 versus 103 M −1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-Δ2-VPA compared with VPA (<<10 versus >20% at total concentrations of less than 100 µg/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin.
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REFERENCES
F. E. Dreifuss, N. Santilli, D. H. Langer, K. P. Sweeney, K. A. Moline, and K. B. Menander. Neurology 37:379–385 (1987).
T. Bjerkedal. International clearing house for birth defects monitoring systems. Lancet 2:1096 (1982).
W. Löscher and H. Nau. Neuropharmacology 24:427–435 (1985).
P. E. Keane, J. Simiand, and M. Morre. Meth. Find. Exp. Clin. Pharmacol. 7:83–86 (1985).
F. S. Abbott and A. Acheampong. Neuropharmacology 27:287–294 (1988).
H. Nau. Teratology 33:21–27 (1986).
C. Lewandowski, S. Klug, H. Nau, and D. Neubert. Arch. Toxicol. 58:239–242 (1986).
J. W. Kesterson, G. R. Granneman, and J. M. Machinist. Hepatology 4:1143–1152 (1984).
H. Schafer and R. Luhrs. In R. H. Levy, W. H. Pitlick, M. Eichelbaum, and J. Meijer (eds.), Metabolism of Antiepileptic Drugs, Raven Press, New York, 1984, pp. 73–81.
U. Klotz and K. H. Antonin. Clin. Pharmacol. Ther. 21:736–743 (1977).
U. Klotz, T. Rapp, and W. A. Muller. Eur. J. Clin. Pharmacol. 13:55–60 (1978).
T. A. Bowdle, I. H. Patel, R. H. Levy, and A. J. Wilensky. Clin. Pharmacol. Ther. 28:486–492 (1980).
H.-Y. Yu, Y.-Z. Shen, Y. Sugiyama, and M. Hanano. Epilepsia 28:680–687 (1987).
H. Nau, H. Helge, and W. Luck. J. Pediat. 104:627–634 (1984).
W. Löscher, H. Nau, and H. Siemes. Epilepsia 29:311–316 (1988).
W. Löscher and H. Nau. Arch. Int. Pharmacodyn. 270:192–202 (1984).
A. Monks and A. Richens. Br. J. Clin. Pharmacol. 8:187–189 (1979).
I. H. Patel and R. H. Levy. Epilepsia 20:85–90 (1979).
C. L. Zimmerman, I. H. Patel, R. H. Levy, D. Edwards, S. D. Nelson, and M. Hutchinson. Epilepsia 22:11–17 (1981).
T. A. Bowdle, I. H. Patel, R. H. Levy, and A. J. Wilensky. Eur. J. Clin. Pharmacol. 23:343–347 (1982).
F. Albani, R. Riva, G. Procaccianti, A. Baruzzi, and E. Perucca. Epilepsia 24:65–73 (1983).
R. Riva, F. Albani, M. Contin, A. Baruzzi, M. Altomare, G. P. Merlini, and E. Perucca. Ther. Drug Mon. 6:25–30 (1984).
K. M. Giacomini, S. Swezey, K. C. Giacomini, and T. F. Blaschke. Life Sci. 27:771–780 (1980).
M. J. Ridd, K. F. Brown, R. G. Moore, and R. L. Nation. Int. J. Pharm. 11:11–20 (1982).
R. Riva, F. Albani, A. Baruzzi, I. Galvani, and E. Perucca. Ther. Drug Mon. 4:341–352 (1982).
P. J. McNamara and J. B. Bogardus. J. Pharm. Sci. 71:1066–1068 (1982).
H. E. Rosenthal. Anal. Biochem. 20:525–532 (1967).
M. Ralston. In W. J. Dixon et al. (eds.), BMDP Statistical Software, University of California Press, Berkeley, 1985, pp. 305–314.
R. L. Priore and H. E. Rosenthal. Anal. Biochem. 70:231–240 (1976).
K. Yamaoka, T. Nakagawa, and T. Uno. J. Pharmacokinet. Biopharm. 6:165–175 (1978).
R. L. O. Semmes and D. D. Shen. J. Chromatogr. 432:185–197 (1988).
K. M. Giacomini, A. Abang, and T. F. Blaschke. Br. J. Clin. Pharmacol. 14:752–753 (1982).
S. R. Bergman, E. Carlson, E. Dannen, and B. E. Sobel. Clin. Chem. Acta 104:53–63 (1980).
B. Rosner. Fundamentals of Biostatistics, Duxbury Press, Boston, 1982, pp. 232–237, 418–424.
B. J. Jordan, J. S. Shillingford, and K. P. Steed. In N. L. Legg (ed.), Clinical and Pharmacological Aspects of Sodium Valproate (Epilim) in the Treatment of Epilepsy, MCS Consultants, Tunbridge Wells, Kent, 1976, pp. 112–118.
J. Barre, J. M. Chamouard, G. Houin, and J. P. Tillement. Clin. Chem. 31:60–64 (1985).
H. Vorum, S. Andersen, and R. Broderson. Epilepsia 30:370–373 (1989).
S. W. M. Koh and G. E. Means. Arch. Biochem. Biophys. 192:73–79 (1979).
D. S. Goodman. J. Am. Chem. Soc. 80:3892–3898 (1958).
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Semmes, R.L.O., Shen, D.D. Nonlinear Binding of Valproic Acid (VPA) and E-Δ2-Valproic Acid to Rat Plasma Proteins. Pharm Res 7, 461–467 (1990). https://doi.org/10.1023/A:1015804413818
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DOI: https://doi.org/10.1023/A:1015804413818