Abstract
Two new structural analogs, 2-(4-hydroxyethoxyphenyl)acetic acid [R3] and 2-(4-hydroxyethoxyphenyl)propionic acid [R4], along with their parent compounds, ibufenac and ibuprofen, were evaluated for their biopharmaceutical properties. The analogs represented substitution of the lipophilic isobutyl side chains of ibufenac and ibuprofen with hydrophilic hydroxyethoxy side chains. Anti-inflammatory activity was evaluated by administering drugs topically to inhibit inflammation induced by using either clove oil or arachidonic acid. The rank order of activity was ibufenac ≅ ibuprofen > R3 ≅ R4. The new compounds, R3 and R4, were highly water soluble (>60-fold) and partitioned less (<1/1500-fold) into the lipid phase when compared to ibufenac and ibuprofen. R3 and R4 each had apparent corneal permeability coefficients of 6×10−6 cm/sec, whereas ibufenac and ibuprofen yielded values of about 22×10−6 cm/sec. In an ocular pharmacokinetic study in the rabbit eye, constant concentrations of each compound were maintained on the cornea in a cylinder or welt fixed to the cornea, resulting in a constant input rate. This method circumvented parallel loss routes at the absorption site including nasolacrimal drainage. From area calculations the dispositions of the compounds within the eye were described by mean residence times, steady state volumes of distributions, and clearance rates. R3 and R4 were more slowly absorbed, retained within eye tissues longer, and were cleared more slowly from the eye than ibufenac and ibuprofen. The aqueous humor concentration-time profiles were also computer-fitted to equations representing classical pharmacokinetic models. For ibufenac and ibuprofen, the entire cornea was assumed to be the net barrier for entry into the anterior chamber. Whereas, for R3 and R4, the corneal epithelium and endothelium were presumed to be the diffusional barriers into and out of the stroma, the latter treated as a compartment. Aqueous humor concentrations of each drug fit the models reasonable well and agreed with conclusions made from the use of area calculations. The drop volume method was used to measure the surface tension of each compound. Both ibufenac and ibuprofen were considerably more surface active than R3 or R4. The greater surface tension measured for ibufenac and ibuprofen correlated to the subjective observations of ocular discomfort for these drugs.
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References
Ophthalmic Drug Facts, J. B. Lippincott, New York, 1989, pp. 136–137.
C. M. Ellingson, R. D. Schoenwald, C. F. Barfknecht, C. S. Rao, and S. L. Laban. Rapid toxicological model for use in assessing ocular drugs.Biopharm. Drug Dispos.,13:461–480 (1992).
S. L. Laban.Chemistry of ophthalmic topical carbonic anhydrase inhibitors, ophthalmic nonsteroidal antiinflammatory agents, and a spiperone-based magnetic resonance image enhancement agent. Ph.D. Thesis, University of Iowa, 1988.
C. Hansch. Appendix I. In W. P. Purcell, G. E. Bass, and J. M. Clayton (eds.),Strategy of Drug Design: A Guide to Biological Activity, Wiley, New York, 1973, pp. 126–133.
G. Gran. Determination of the equivalent point in potentiometric titrations.Acta Chem. Scand. 4:559–577 (1950).
G. Gran. Determination of the equivalence point in potentiometric titrations. Part II.Analyst 77:661–671 (1952).
R. C. Weast (ed.).CRC Handbook of Chemistry and Physics, 1st Student edition, CRC Press Inc., Boca Raton, FL, 1988, p. F-14.
W. D. Harkins and F. E. Brown. The determination of surface tension (free surface energy), and the weight of falling drops: The surface tension of water and benzene by the capillary height method.J. Am. Chem. Soc. 41:499–524 (1919).
W.J. O'Brien and H. F. Edelhauser. The corneal penetration of trifluorothymidine, adenine arabinoside, and idoxuridine: A comparative study.Invest. Ophthalmol. Vis. Sci. 16:1093–1103 (1977).
R. D. Schoenwald and H.-S. Huang. Corneal penetration behavior ofΒ-blocking agents. I: Physicochemical factors.J. Pharm. Sci. 72:1266–1272 (1983).
H. M. Leibowitz, J. H. Lass, and A. Kupferman. Quantitation of inflammation in the cornea.Arch. Ophthalmol. 92:427–430 (1974).
M. B. Abelson, S. I. Butrus, G. H. Kliman, D. L. Larson, E. J. Corey, and L. M. Smith. Topical arachidonic acid: A model for screening antiinflammatory agents.J. Ocul. Pharmacol. 3:63–75 (1987).
M. G. Eller, R. D. Schoenwald, J. A. Dixson, T. Segarra, and C. F. Barfknecht. Topical carbonic anhydrase inhibitors. IV: Relationship between excised corneal permeability and pharmacokinetic factors.J. Pharm. Sci. 74:525–529 (1985).
G. F. Lockwood and J. G. Wagner. High-performance liquid chromatographic determination of ibuprofen and its major metabolites in biological fluids.J. Chromatog. 232:335–343 (1982).
R. D. Schoenwald. Ocular drug delivery: Pharmacokinetic considerations.Clin. Pharmacokin. 18:255–269 (1990).
K. Green and A. M. Tonjum. The effect of benzalkonium chloride on the electropotential of the rabbit cornea.Acta Ophthalmol. 53:348–357 (1975).
B. O. Hedbys and S. Mishima. The thickness-hydration relationship of the cornea.Exp. Eye Res. 5:221–228 (1966).
R. J. Flower, S. Moncada, and J. R. Vane. Analgesic antipyretics and antiinflammatory agents. Drugs employed in the treatment of gout. In A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad (eds.),The Pharmacologic Basis of Therapeutics, 7th ed., Macmillan, New York, 1985, pp. 701–702.
M. W. Whitehouse and K. D. Rainsford. Esterification of acidic anti-inflammatory drugs suppresses their gastrotoxicity without adversely affecting their anti-inflammatory activity in rats.J. Pharm. Pharmacol. 32:795–796 (1980).
S. S. Adams, P. Hebborn, and J. S. Nicholson. Some aspects of the pharmacology of ibufenac, a non-steroidal anti-inflammatory agent.J. Pharm. Pharmacol. 20:305–312 (1968).
M. Hollander and D. A. Wolfe. InNonparametric Statistical Methods, Wiley, New York, 1973, pp. 26–35.
R. D. Schoenwald and D.-S. Chien. Ocular absorption and disposition of phenylephrine and phenylephrine oxazolidine.Biopharm. Drug Dispos. 9:527–538 (1988).
C.-H. Chiang and R. D. Schoenwald. Ocular pharmacokinetic models of clonidine-3H hydrochloride.J. Pharmacokin. Biopharm. 14:175–211 (1986).
RSTRIP—Polyexponential Curve Stripping/Least Squares Parameter Estimation Program, MicroMath Scientific Software, Salt Lake City, UT, 1991.
V. H.-L. Lee and J. R. Robinson. Mechanistic and quantitative evaluation of precorneal pilocarpine disposition in albino rabbits.J. Pharm. Sci. 68:673–684 (1979).
S. C. Miller, K. J. Himmelstein, and T. F. Patton. A physiologically based pharmacokinetic model for the intraocular distribution of pilocarpine in rabbits.J. Pharmacokin. Biopharm. 9:653–677 (1981).
D. D.-S. Tang-Liu, S. S. Liu, and R. J. Weinkam. Ocular and systemic bioavailability of ophthalmic flurbiprofen.J. Pharmacokin. Biopharm. 12:611–626 (1984).
D. M. Maurice. Structures and fluids involved in the penetration of topically applied drugs. In F. J. Holly (ed.),Clinical Pharmacology of the Anterior Segment, Little, Brown, Boston, 1980, pp. 7–20.
J. M. Conrad and J. R. Robinson. Aqueous chamber drug distribution volume measurement in rabbits.J. Pharm. Sci. 66:219–224 (1977).
BMDP AR. PC-90.BMDP Statistical Software Inc., Los Angeles, CA.
M. Gibaldi and D. Perrier. InPharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982, pp. 33–36.
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This work was abstracted in part from a Ph.D. thesis submitted by Chakradhara S. Rao to the Graduate College, The University of Iowa. It was supported by Angelini Pharmaceuticals, Inc., River Edge, New Jersey 07661.
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Rao, C.S., Schoenwald, R.D., Barfknecht, C.F. et al. Biopharmaceutical evaluation of ibufenac, ibuprofen, and their hydroxyethoxy analogs in the rabbit eye. Journal of Pharmacokinetics and Biopharmaceutics 20, 357–388 (1992). https://doi.org/10.1007/BF01062463
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DOI: https://doi.org/10.1007/BF01062463