Abstract
The potential bioavailability improvement of mycophenolic acid (MPA), 1, through ester derivatization was evaluated in monkeys at a dose of 20 mg/kg in this study. The acetyl solketal ester 3 was found to have excellent partition properties but poor aqueous solubility. Thus, even though it can be converted rapidly to MPA by plasma and liver enzymes, it showed poor oral bioavailability (56% of MPA) in monkeys. The bioavailability of the morpholinoethyl ester 4 and the acetyl morpholinoethyl ester 5, on the other hand, was found to be 236 and 150% that of MPA, respectively. Since ester 5 has greater aqueous solubility, but similar chemical stability and enzymatic hydrolysis rates compared to ester 4, the better bioavailability of ester 4 may result from its greater partitioning into the gastrointestinal membranes.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
B. Gosio. Riv. Igiene Sanita Pub. Ann. 7:825–831 (1896).
D. F. Jones and S. D. Mills. J. Med. Chem. 14:305–311 (1971).
D. J. Hupe, B. A. Azzolina, and N. D. Behrens. J. Bio. Chem. 261:8363–8369 (1986).
W. W. Epinette, C. M. Parker, E. L. Jones, and M. C. Greist. J. Am. Acad. Dermatol. 17:962–971 (1987).
Y. Ohsugi, S. Suzuki, and Y. Takagaki. Cancer Res. 36:2923–2927 (1976).
P. H. Nelson, A. C. Allison, and E. M. Eugui. U.S. Patent 4686234, Aug. (1987).
H. Mitsui, T. Matsuno, H. Ogawa, T. Shiio, Y. Yugari, and G. Tamura. Gann 72:66–71 (1981).
Y. Matsuzawa and T. Nakase. J. Pharm. Dyn. 7:776–783 (1984).
A. F. Hegarty, L. N. Frost, and J. H. Coy. J. Org. Chem. 39:1089–1093 (1974).
A. Albert and E. P. Serjeant. The Determination of Ionization Constants, 2nd ed., Chapman and Hall, London, 1971.
R. Nery and E. Nice. J. Pharm. Pharmacol. 23:842–847 (1971).
M. J. Sweeney, D. H. Hoffman, and M. A. Esterman. Cancer Res. 32:1803–1809 (1972).
R. Ito, T. Nagami, T. Yasuda, H. Tsutsume, Y. Tojima, Y. Matsuno, S. Yoshida, and S. Akaboshi. J. Med. Soc. Toho Jap. 29:412–418 (1982).
L. Gu and R. G. Strickley. Pharm. Res. 4:255–257 (1987).
R. Runkel, M. Chaplin, G. Boost, E. Segre, and E. Forchielli. J. Pharm. Sci. 61:703–108 (1972).
W. E. Hamlin, J. I. Northam, and J. G. Wagner. J. Pharm. Sci. 54:1651–1653 (1965).
S. H. Unger, J. R. Cook, and J. S. Hollenberg. J. Pharm. Sci. 67:1364–1367 (1978).
P. H. Nelson, L. Gu, A. C. Allison, E. M. Eugui and W. A. Lee. U.S. Patents 4,727,069 (1988).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lee, W.A., Gu, L., Miksztal, A.R. et al. Bioavailability Improvement of Mycophenolic Acid Through Amino Ester Derivatization. Pharm Res 7, 161–166 (1990). https://doi.org/10.1023/A:1015828802490
Issue Date:
DOI: https://doi.org/10.1023/A:1015828802490