Development of simultaneous quantification method of loteprednol etabonate (LE) and its acidic metabolites, and analysis of LE metabolism in rat

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Date

2019

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Article

Publisher

Taylor & Francis

Series Info

Xenobiotica;Volume: 49 Issue: 5 Pages: 569-576

Abstract

Loteprednol etabonate (LE) is a soft corticosteroid with two labile ester bonds at 17α- and 17β-positions. Its corticosteroidal activity disappears upon hydrolysis of either ester bond. Hydrolysis of both ester bonds produces the inactive metabolite, Δ1-cortienic acid (Δ1-CA). The simple high-performance liquid chromatography method using acetic acid gradient was developed for the simultaneous determination of LE and its acidic metabolites. LE was hydrolyzed in rat plasma with a half-life of 9 min. However, LE hydrolysis was undetectable in rat liver and intestine. LE hydrolysis in rat plasma was completely inhibited by paraoxon and bis(p-nitrophenyl) phosphate, thus identifying carboxylesterase as the LE hydrolase. Rat plasma carboxylesterase had a Km of 6.7 μM for LE. In contrast to the disappearance rate of LE in rat plasma, the formation rate of 17α-monoester and Δ1-CA was markedly low, and a main hydrolysate of LE was not detected in rat plasma. The metabolism of LE proceeded via different pathways in human and rat plasma. LE was slowly hydrolyzed by paraoxonase in human plasma to 17α-monoester with a half-life of 12 h, but by carboxylesterase in rat plasma to yield undetectable products, presumed to include the unstable 17β-monoester.

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MSA Google Scholar

Keywords

University of Metabolite determination, loteprednol etabonate, high-performance liquid chromatography, rat plasma, hydrolysis, carboxylesterase

Citation

Amon M, Busin M. (2012). Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use. Int Ophthalmol 32:507–17. [Crossref], [PubMed], [Google Scholar] Bahar FG, Ohura K, Ogihara T, Imai T. (2012). Species difference of esterase expression and hydrolase activity in plasma. J Pharm Sci 101:3979–88. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Berry LM, Wollenberg L, Zhao Z. (2009). Esterase activities in the blood, liver and intestine of several preclinical species and humans. Drug Metab Lett 3:70–7. [Crossref], [PubMed], [Google Scholar] Bodor N, Bodor N, Wu WM. (1992a). A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits. Curr Eye Res 11:525–30. [Taylor & Francis Online], [Web of Science ®], [Google Scholar] Bodor N, Buchwald P. (2000). Soft drug design: general principles and recent applications. Med Res Rev 20:58–101. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Bodor N, Buchwald P. (2002). Design and development of a soft corticosteroids, lotepredonol etabonate. In: Schleimer RP, O’Byrne PM, Szefler SJ, Brattsand R, eds. Inhaled steroid in asthma. Optimizing effects in the airways. New York, NY: Marcel Dekker, 541–64. [Google Scholar] Bodor N, Buchwald P. (2004). Designing safer (soft) drugs by avoiding the formation of toxic and oxidative metabolites. Mol Biotechnol 26:123–32. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Bodor N, Buchwald P. (2005). Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems. AAPS J 7:E820–33. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Bodor N, Buchwald P. (2006). Corticosteroid design for the treatment of asthma: structural insights and the therapeutic potential of soft corticosteroids. Curr Pharm Des 12:3241–60. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Bodor N, Loftsson T, Wu WM. (1992b). Metabolism, distribution, and transdermal permeation of a soft corticosteroid, loteprednol etabonate. Pharm Res 9:1275–8. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Bodor N, Murakami T, Wu WM. (1995a). Soft drugs. 18. Oral and rectal delivery of loteprednol etabonate, a novel soft corticosteroid, in rats–for safer treatment of gastrointestinal inflammation. Pharm Res 12:869–874. [Google Scholar] Bodor N, Wu WM, Murakami T, Engel S. (1995). Soft drugs. 19. Pharmacokinetics, metabolism and excretion of a novel soft corticosteroid, loteprednol etabonate, in rats. Pharm Res 12:875–9. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Bradford MM. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–54. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Buchwald P, Bodor N. (2004). Soft glucocorticoid design: structural elements and physicochemical parameters determining receptor-binding affinity. Pharmazie 59:396–404. [PubMed], [Web of Science ®], [Google Scholar] Druzgala P, Hochhaus G, Bodor N. (1991a). Soft drugs 10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate. J Steroid Biochem Mol Biol 38:149–54. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Druzgala P, Wu WM, Bodor N. (1991). Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res 10:933–7. [Taylor & Francis Online], [Web of Science ®], [Google Scholar] Food and Drug Administration. (1997). International Conference on Harmonization (ICH), Q2b: Validation of Analytical Procedures: Methodology. 62 FR 27463. Federal Registry, 19 May 1997. [Google Scholar] Howes JF. (2000). Loteprednol etabonate: a review of ophthalmic clinical studies. Pharmazie 55:178–83. [PubMed], [Web of Science ®], [Google Scholar] Ilyas H, Slonim CB, Braswell GR, et al. (2004). Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye Contact Lens 30:10–3. [Crossref], [PubMed], [Google Scholar] Li B, Sedlacek M, Manoharan I, et al. (2005). Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma. Biochem Pharmacol 70:1673–84. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Ohura K, Tasaka K, Hashimoto M, Imai T. (2014). Distinct patterns of aging effects on the expression and activity of carboxylesterases in rat liver and intestine. Drug Metab Dispos 42:264–73. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Samir A, Bodor N, Imai T. (2017). Identification of esterase involved in the metabolism of two corticosteroid soft drugs. Biochem Pharmacol 127:82–9. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Wu WM, Huang F, Lee Y, et al. (2008). Pharmacokinetics of the sequential metabolites of loteprednol etabonate in rats. J Pharm Pharmacol 60:291–7. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Wu WM, Tang Y, Buchwald P, Bodor N. (2010). Pharmacokinetics and delta1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats. Pharmazie 65:412–6. [PubMed], [Web of Science ®], [Google Scholar] Yamaoka K, Nakagawa T. (1983). A nonlinear least squares program based on differential equations, MULTI (RUNGE), for microcomputers. J Pharmacobiodyn 6:595–606.

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