Abstract
Purpose. To investigate a novel approach for the determination of liposomal membrane-water partition coefficients and lipophilicity profiles of ionizable drugs.
Methods. The measurements were performed by using a pH-metric technique in a system consisting of dioleylphosphatidylcholine (DOPC) unilamellar vesicles in 0.15 M KC1 at 25°C. The DOPC unilamellar vesicle suspension was prepared via an extrusion process.
Results. The liposomal membrane-water partition coefficients of eight ionizable drugs: ibuprofen, diclofenac, 5-phenylvaleric acid, warfarin, propranolol, lidocaine, tetracaine and procaine were determined and the values for neutral and ionized species were found to be in the ranges of approximately 4.5 to 2.4 and 2.6 to 0.8 logarithmic units, respectively.
Conclusions. It has been shown that the liposomal membrane-water partition coefficients as derived from the pH-metric technique are consistent with those obtained from alternative methods such as ultrafiltration and dialysis. It was found that in liposome system, partitioning of the ionized species is significant and is influenced by electrostatic interaction with the membranes. We have demonstrated that the pH-metric technique is an efficient and accurate way to determine the liposomal membrane-water partition coefficients of ionizable substances.
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REFERENCES
U. Hacksell. Structural and Physícochemical Factors in Drug Action. In P. Krogsgaard-Larsen, T. Liljefors and U. Madsen (eds.), A Text Book of Drug Design and Development, Harwood Academic Publisher, Amsterdam, 1996, pp. 35–59.
J. J. Kaufman, N. M. Semo, and W. S. Koski. J. Med. Chem. 18:647–655 (1975).
A. Leo, C. Hansch, and D. Elkins. Chem. Rev. 71:525–616 (1971).
J. K. Seydel and K. J. Schaper. In M. Rowland and G. T. Tucker (eds.), Pharmacokinetics: Theory and Methodology; Pergamon Press, Oxford, 1986; pp. 331–366.
U. Hellwich and R. Schubert. Biochem. Pharmacol. 49:511–517 (1995).
J. Miyazaki, K. Hideg, and D. Marsh. Biochim. Biophys. Acta 1103:62–68 (1992).
R. P. Austin, A. M. Davis, and C. N. Manners. J. Pharm. Sci. 84:1180–1183 (1995).
G. Schwarz. Biophys. Chem. 58:67–73 (1996).
M. Foradada and J. Estelrich. Int. J. Pharm. 124:261–269 (1995).
M. R. Wenk, A. Fahr, R. Reszka, and J. Seelig. J. Pharm. Sci. 85:228–231 (1996).
J. A. Rogers and Y. W. Choi. Pharm. Res. 10:913–917 (1993).
S. Ong, H. Liu, X. Qiu, G. Bhat, and C. Pidgeon. Anal. Chem. 67:755–762 (1995).
C. Pidgeon, S. Ong, H. Liu, X. Qiu, M. Pidgeon, A. H. Dantzig, J. Munroe, J. Hornback, J. S. Kasher, L. Glunz, and T. Szczerba. J. Med. Chem. 38:590–594 (1995).
J. Formelova, A. Breier, P. Gemeiner, and L. Kurillova. Coll. Czech. Chem. Comm. 56:712–717 (1991).
W. N. Kuhnvelten. Eur. J. Biochem. 197:381–390 (1991).
G. M. Pauletti and H. Wunderli-Allenspach. Eur. J. Pharm. Sci. 1:273–282 (1994).
A. Avdeef. Quant. Struct.—Act. Relat. 11:510–517 (1992).
A. Avdeef. J. Pharm. Sci. 82:183–190 (1993).
A. Avdeef, J. E. A. Comer and S. J. Thomson. Anal. Chem. 65:42–49 (1993).
B. Slater, A. McCormack, A. Avdeef, and J. E. A. Comer. J. Pharm. Sci. 83:1280–1283 (1994).
K. Takács-Novák, A. Avdeef, and K. J. Box. J. Pharm. Biomed. Anal. 12:1369–1377 (1994).
A. Avdeef, K. J. Box, and K. Takács-Nováks. J. Pharm. Sci. 84:523–529 (1995).
A. Avdeef, D. A. Barrett, P. N. Shaw, R. D. Knaggs, and S. S. Davis. J. Med. Chem. 39:4377–4381 (1996).
A. Avdeef. Assessment of distribution-pH profiles. In V. Pliska, B. Testa and H. van de Waterbeemd (eds.), Lipophilicity in Drug Action and Toxicology, VCH, Weinhem, 1996, pp. 109–137.
K. Takács-Novák and A. Avdeef. J. Pharm. Biomed. Anal. 14:1405–1413 (1996).
M. J. Hope, M. B. Bally, G. Webb, and P. R. Cullis. Biochim. Biophys. Acta 812:55–65 (1985).
L.D. Mayer, M. J. Hope, and P. R. Cullis. Biochim. Biophys. Acta 858:161–168 (1986).
A. Avdeef and J. J. Bucher. Anal. Chem. 50:2137–2142 (1987).
C. Ottiger and H. Wunderli-Allenspach. Partition behaviour of acids and bases in a phosphatidylcholine liposome/buffer equilibrium dialysis system. Eur. J. Pharm. Sci. (in press).
Y. Boulanger, S. Schreier, L. C. Leitch, and I. C. P. Smith. Can. J. Biochem. 58:986–995 (1980).
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Avdeef, A., Box, K.J., Comer, J.E.A. et al. pH-Metric logP 10. Determination of Liposomal Membrane-Water Partition Coefficients of lonizable Drugs. Pharm Res 15, 209–215 (1998). https://doi.org/10.1023/A:1011954332221
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DOI: https://doi.org/10.1023/A:1011954332221