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Response to the Commentary on “Pharmacokinetic Characterization and Tissue Distribution of the New Glucocorticoid Soft Drug Loteprednol Etabonate in Rats and Dogs”
Response to the Commentary on “Pharmacokinetic Characterization and Tisswe Distribution of the New Glucocorticoid Soft Drug Loteprednol Etabonate in Rats and Dogs”
To the Editor: A commentary, submitted to the Journal by two members of our College of Pharmacy, questions both the general drug-design concept for soft steroids and the specific design of loteprednol etabonate (1). The commentary is directed toward our pharmacolrinetic evaluation of 1 that was published last year in the Journal.’ Specifically queried is the relative importance of hydrolysis in plasma versus liver and the role of plasma protein binding in the design of soft steroids for topical use. While four of our publications are cited,14 unfortunately the commentary fails t o reference the principle publications that describe the concepts involved in soft-drug design. The design concepts for soft drugs were first published in 1980: and various classeri of soft drugs were described in 1982.6 Additionally, numerous examples for the various classes of soft steroids along with synthesis and preliminary results appeared in the patent literature a dozen years Several subsequent reviews summarize the types of soft-drug-design strategies and their applic,rition to steroidsl1° One of these soft-drug strategies, the ”inactive metabolite” appronch, served as the basis for designing 1. The inactive A’cortieriic acid (2) was chemically modified to form an active corticosteroid that could be metabolized to the inactive 17acarbonate and then back to 2. A fundamental aspect of design involvedthe predicted metabolism of the 178-chloromethylester to the inactive A’-cortienic acid derivative. The speed of plasma hydrolysis is not the principle factor in designing soft steroids according to the inactive-metabolite strategy. The systemically absorbed drug that we measured’ refers to soft steroid which entered the circulation from the topical application site. While the extent of systemic absorption is reflected in plasma levels, it does not imply metabolic inactivation by the plasma enzymes. In contrast, the postabsorption disposition is consistent with inactivation by blood or tissue enzyme systems, independent of the mechanism. OH
soft steroids synthesized? the predicted hydrolytic inactivation of anticholinergic and P-adrenergic blocking agents, designed as soft drugs, was shown to be structure dependent and to proceed at very different rates for various tissues.gJ1J2 Studies showed that ocular administration of 1in rabbits resulted in the predicted cortienic acid-type metabolites in all compartments of the eye.13 Our distribution studies with 1showed high tissue concentrations after systemic dosing and liver metabolite levels that support hepatic inactivation.’ As expected, based on the well-known relative enzyme activity differences between rodents and higher species,kinetic parameters for loteprednol were different between rats and Moreover, results were consistent with our previous publication from 1988 that explained the importance of hepatic inactivation: The high concentrations of both 1 and its metabolites, in the liver, indicate that this organ is the main site of metabolism.”SJ The high first-pass effect of 1 after oral delivery to dogs further demonstrated the importance of the liver as a main metabolic organ; it is therefore rather difficult to understand why the commentary suggests that complete extraction by the liver has been overlooked. The commentary regarding protein binding is puzzling. Indeed, the design of 1considered characteristics important for transcortin binding and we demonstrated this binding.2 An important aspect of our pharmacokinetic evaluation studied protein binding: consequently our discussion stresses that the high level of bound drug clearly reduces free active steroid available for unwanted systemic effects. However, clearance of high-extraction drugs is understood to be primarily a function of blood flow and is independent of protein binding. Thus, high protein binding is not the essential key in successful soft-drug design as suggested in the commentary. High clearance could also sufficiently decrease systemically absorbed drug below ranges associated with systemic side effects. The conclusions drawn in the commentary acknowledge the “soft” structure of 1 and its therapeutic value as a topical corticosteroid. While we respect the general importance of scientific commentaries, it is clear that the comments offered by our colleagues do not reflect a first-hand knowledge of softdrug-design principles. We are unaware of any publications on relevant soft-drug design authored by either of the individuals. The commentary reflects a casual reading or misunderstanding of the relevant literature which is indicated by the use of selective and misleading quotations. Concise and clear explanations of the soft-drug-designprinciples that we applied to develop topical steroids with an improved therapeutic index are presented in severalpublications.”’O These design principles are summarized in Korolkovas’ widely used textbook, “Essentials of Medicinal Chemistry”.14
Lowprednol Etabonau
References Cited
u) OH
I
c-0
1. Hochhaus,G.;Chen,L.S.;Ratka,A.;Druzgala,P.;Howes,J.;Bodor, N.; Derendorf, H. J. Pharm. Sci. 1992,81, 121G1215. 2. Druzgala, P.; Hochhaus, G.; Bodor, N. J. Steroid Biochem. Mol. Biol. 1991, 38, 149-154. 3. Bodor, N.; Loftsson, T.; Wu, W-M. Pharm. Res. 1992, 9, 1275-
OH
1278.
Design factors for soft drugs usually prefer a hydrolytic metabolism as opposed to oxidation. Similar to the numerous 0 1994, American Chemical Society and American Pharmaceutical Association
4. Druzgala, P. New Soft Antiinflammatory Glucocorticoids for Topical Applications, Ph.D. Dissertation, University of Florida, Gainesville,FL, 1985. 5. Bodor, N.; Kaminski, J. J.; Selk, S. H. J. Med. Chern. 1980, 23, 469-474.
0022-3549/94/1200- 1067$04.50/0
Journal of Pharmaceutical Sciences / 1087 Vol. 83, No. 7, July 1994
6. Bodor, N. Trends. Pharrn. Sci. 1982,3,53-56. 7. Bodor,N.Belg.BE889,563 (Cl.CO73),Nov.3,1981;UKPat.207955,
July 6,1981. 8. Bodor, N. In Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs; Christophers, E., et al., Eds.; Raven Press, La.: New York, 1988; pp 13-25. 9. Bodor, N. In Trends in Medicinal Chemistry '88; van der Goot, H., Domany, G., Pallos, L., Timmerman, H., Eds.; Elsevier Science Publishers, B. V.: Amsterdam, 1989;pp 145-164. 10. Bodor, N. Med. Res. Rev. 1984,4,449-469. 11. Bodor, N.; El-Koussi, A.; Kano, M.; Khalifa, M. J. Med. Chem. 1988,31,1651-1656. 12. Kumar, G.;Hammer, R.; Bodor, N. Drug Design Discou. 1993.10, 11-21. 13. Druzgala, P.;Wu, W-M.; Bodor, N. Curr. Eye Res. 1991,10,933937. 14. Korolkovas, A. In Essentials of Medicinal Chemistry; 2nd ed.; John Wiley & Sons: New York, 1988;pp 92-97.
1060 / J m a l of phermaceutical Sciences Vol. 83, No. 7. July 1994
GUENTHER HOCHHAUS'~ PASCALDRUZGALA~ JOHNF. HOWES~ NICHOLASBODOR§ HARTMUT DERENDORF' 'Department of Pharmaceutlcs University of Florida Gainesville, FL 32610-0494 Wtarmos Corporation Alachua, FL Center for Drug Discovery University of Florida Received November 16. 1993. Accepted for publication January 7, 1994.
To the Editor: A commentary, submitted to the Journal by two members of our College of Pharmacy, questions both the general drug-design concept for soft steroids and the specific design of loteprednol etabonate (1). The commentary is directed toward our pharmacolrinetic evaluation of 1 that was published last year in the Journal.’ Specifically queried is the relative importance of hydrolysis in plasma versus liver and the role of plasma protein binding in the design of soft steroids for topical use. While four of our publications are cited,14 unfortunately the commentary fails t o reference the principle publications that describe the concepts involved in soft-drug design. The design concepts for soft drugs were first published in 1980: and various classeri of soft drugs were described in 1982.6 Additionally, numerous examples for the various classes of soft steroids along with synthesis and preliminary results appeared in the patent literature a dozen years Several subsequent reviews summarize the types of soft-drug-design strategies and their applic,rition to steroidsl1° One of these soft-drug strategies, the ”inactive metabolite” appronch, served as the basis for designing 1. The inactive A’cortieriic acid (2) was chemically modified to form an active corticosteroid that could be metabolized to the inactive 17acarbonate and then back to 2. A fundamental aspect of design involvedthe predicted metabolism of the 178-chloromethylester to the inactive A’-cortienic acid derivative. The speed of plasma hydrolysis is not the principle factor in designing soft steroids according to the inactive-metabolite strategy. The systemically absorbed drug that we measured’ refers to soft steroid which entered the circulation from the topical application site. While the extent of systemic absorption is reflected in plasma levels, it does not imply metabolic inactivation by the plasma enzymes. In contrast, the postabsorption disposition is consistent with inactivation by blood or tissue enzyme systems, independent of the mechanism. OH
soft steroids synthesized? the predicted hydrolytic inactivation of anticholinergic and P-adrenergic blocking agents, designed as soft drugs, was shown to be structure dependent and to proceed at very different rates for various tissues.gJ1J2 Studies showed that ocular administration of 1in rabbits resulted in the predicted cortienic acid-type metabolites in all compartments of the eye.13 Our distribution studies with 1showed high tissue concentrations after systemic dosing and liver metabolite levels that support hepatic inactivation.’ As expected, based on the well-known relative enzyme activity differences between rodents and higher species,kinetic parameters for loteprednol were different between rats and Moreover, results were consistent with our previous publication from 1988 that explained the importance of hepatic inactivation: The high concentrations of both 1 and its metabolites, in the liver, indicate that this organ is the main site of metabolism.”SJ The high first-pass effect of 1 after oral delivery to dogs further demonstrated the importance of the liver as a main metabolic organ; it is therefore rather difficult to understand why the commentary suggests that complete extraction by the liver has been overlooked. The commentary regarding protein binding is puzzling. Indeed, the design of 1considered characteristics important for transcortin binding and we demonstrated this binding.2 An important aspect of our pharmacokinetic evaluation studied protein binding: consequently our discussion stresses that the high level of bound drug clearly reduces free active steroid available for unwanted systemic effects. However, clearance of high-extraction drugs is understood to be primarily a function of blood flow and is independent of protein binding. Thus, high protein binding is not the essential key in successful soft-drug design as suggested in the commentary. High clearance could also sufficiently decrease systemically absorbed drug below ranges associated with systemic side effects. The conclusions drawn in the commentary acknowledge the “soft” structure of 1 and its therapeutic value as a topical corticosteroid. While we respect the general importance of scientific commentaries, it is clear that the comments offered by our colleagues do not reflect a first-hand knowledge of softdrug-design principles. We are unaware of any publications on relevant soft-drug design authored by either of the individuals. The commentary reflects a casual reading or misunderstanding of the relevant literature which is indicated by the use of selective and misleading quotations. Concise and clear explanations of the soft-drug-designprinciples that we applied to develop topical steroids with an improved therapeutic index are presented in severalpublications.”’O These design principles are summarized in Korolkovas’ widely used textbook, “Essentials of Medicinal Chemistry”.14
Lowprednol Etabonau
References Cited
u) OH
I
c-0
1. Hochhaus,G.;Chen,L.S.;Ratka,A.;Druzgala,P.;Howes,J.;Bodor, N.; Derendorf, H. J. Pharm. Sci. 1992,81, 121G1215. 2. Druzgala, P.; Hochhaus, G.; Bodor, N. J. Steroid Biochem. Mol. Biol. 1991, 38, 149-154. 3. Bodor, N.; Loftsson, T.; Wu, W-M. Pharm. Res. 1992, 9, 1275-
OH
1278.
Design factors for soft drugs usually prefer a hydrolytic metabolism as opposed to oxidation. Similar to the numerous 0 1994, American Chemical Society and American Pharmaceutical Association
4. Druzgala, P. New Soft Antiinflammatory Glucocorticoids for Topical Applications, Ph.D. Dissertation, University of Florida, Gainesville,FL, 1985. 5. Bodor, N.; Kaminski, J. J.; Selk, S. H. J. Med. Chern. 1980, 23, 469-474.
0022-3549/94/1200- 1067$04.50/0
Journal of Pharmaceutical Sciences / 1087 Vol. 83, No. 7, July 1994
6. Bodor, N. Trends. Pharrn. Sci. 1982,3,53-56. 7. Bodor,N.Belg.BE889,563 (Cl.CO73),Nov.3,1981;UKPat.207955,
July 6,1981. 8. Bodor, N. In Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs; Christophers, E., et al., Eds.; Raven Press, La.: New York, 1988; pp 13-25. 9. Bodor, N. In Trends in Medicinal Chemistry '88; van der Goot, H., Domany, G., Pallos, L., Timmerman, H., Eds.; Elsevier Science Publishers, B. V.: Amsterdam, 1989;pp 145-164. 10. Bodor, N. Med. Res. Rev. 1984,4,449-469. 11. Bodor, N.; El-Koussi, A.; Kano, M.; Khalifa, M. J. Med. Chem. 1988,31,1651-1656. 12. Kumar, G.;Hammer, R.; Bodor, N. Drug Design Discou. 1993.10, 11-21. 13. Druzgala, P.;Wu, W-M.; Bodor, N. Curr. Eye Res. 1991,10,933937. 14. Korolkovas, A. In Essentials of Medicinal Chemistry; 2nd ed.; John Wiley & Sons: New York, 1988;pp 92-97.
1060 / J m a l of phermaceutical Sciences Vol. 83, No. 7. July 1994
GUENTHER HOCHHAUS'~ PASCALDRUZGALA~ JOHNF. HOWES~ NICHOLASBODOR§ HARTMUT DERENDORF' 'Department of Pharmaceutlcs University of Florida Gainesville, FL 32610-0494 Wtarmos Corporation Alachua, FL Center for Drug Discovery University of Florida Received November 16. 1993. Accepted for publication January 7, 1994.