PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
AAPS PharmSciTech. 2007 September; 8(3): E28–E33.
Published online 2007 July 13. doi:  10.1208/pt0803055
PMCID: PMC2750551

Transbuccal delivery of 5-Aza-2′-deoxycytidine: Effects of drug concentration, buffer solution, and bile salts on permeation

Abstract

Delivery of 5-aza-2′-deoxycytidine (decitabine) across porcine buccal mucosa was evaluated as an alternative to the complex intravenous infusion regimen currently used to administer the drug. A reproducible high-performance liquid chromatography method was developed and optimized for the quantitative determination of this drug. Decitabine showed a concentration-dependent passive diffusion process across porcine buccal mucosa. An increase in the ionic strength of the phosphate buffer from 100 to 400 mM decreased the flux from 3.57±0.65 to 1.89±0.61 μg/h/cm2. Trihydroxy bile salts significantly enhanced the flux of decitabine at a 100 mM concentration (P>.05). The steady-state flux of decitabine in the presence of 100 mM of sodium taurocholate and sodium glycocholate was 52.65±9.48 and 85.22±7.61 μg/cm2/h, respectively. Two dihydroxy bile salts, sodium deoxytaurocholate and sodium deoxyglycocholate, showed better enhancement effect than did trihydroxy bile salts. A 38-fold enhancement in flux was achieved with 10 mM of sodium deoxyglycocholate.

Keywords: Decitabine, transmucosal, buccal, ionic strength, bile salts

Full Text

The Full Text of this article is available as a PDF (171K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20:85–93. doi: 10.1016/0092-8674(80)90237-8. [PubMed] [Cross Ref]
2. Bouchard J, Momparler RL. Incorporation of 5-aza-2′-deoxycytidine-5′-triphosphate into DNA. Interactions with mammalian DNA polymerase alpha and DNA methylase. Mol Pharmacol. 1983;24:109–114. [PubMed]
3. Pinto A, Attadia V, Fusco A, Ferrara F, Spada OA, Di Fiore PP. 5-Aza-2′-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood. 1984;64:922–929. [PubMed]
4. Rivard GE, Momparler RL, Demers J. Phase 1 study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leuk Res. 1981;5:453–462. doi: 10.1016/0145-2126(81)90116-8. [PubMed] [Cross Ref]
5. Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther. 1985;30:277–286. doi: 10.1016/0163-7258(85)90052-X. [PubMed] [Cross Ref]
6. Richel DJ, Colly LP, Kluin-Nelemans JC, Willemze R. The antileukaemic activity of 5-aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia. Br J Cancer. 1991;64:144–148. [PMC free article] [PubMed]
7. Kantarjian HM, O'Brien SM, Estey E, et al. Decitabine studies in chronic and acute myelogenous leukemia. Leukemia. 1997;11:S35–S36. doi: 10.1038/sj.leu.2400796. [PubMed] [Cross Ref]
8. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2′-deoxycytidine (decitabine) treatment. Blood. 2002;100:2957–2964. doi: 10.1182/blood.V100.8.2957. [PubMed] [Cross Ref]
9. Zagonel V, Lo Re G, Marotta G, et al. 5-Aza-2′-deoxycytidine (decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. Leukemia. 1993;7:30–35. [PubMed]
10. Koshy M, Dorn L, Bressler L, et al. 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood. 2000;96:2379–2384. [PubMed]
11. Cunha KS, Reguly ML, Graf U, de Andrade HH. Somatic recombination: a major genotoxic effect of two pyrimidine antimetabolitic chemotherapeutic drugs in Drosophila melanogaster. Mutat Res. 2002;514:95–103. [PubMed]
12. Momparler LF. 5-Aza-2-deoxycytidine: an overview. In: Momparler RL, De Vos D, editors. Proceedings of the Workshop on 5-Aza-2-Deoxycytidine. New York, NY: PCH Publication; 1990. pp. 9–15.
13. Pinto A, Zagonel V. 5-Aza-2′-deoxycytidine (decitabine) and 5-azacytidine in the treatment of acute myeloid leukemias and myelodysplastic syndromes: past, present and future trends. Leukemia. 1993;7:51–60. [PubMed]
14. Richel DL, Colly LP, Lurvink E, Willemze R. Comparison of the antileukemic activity of 5-aza-2-deoxycytidine (5-aza-dC) and 1-d-arabinofuranosylcytosine in rats with araC resistant and sensitive myelocytic leukemia. In: Momparler RL, De Vos D, editors. Proceedings of the Workshop on 5-Aza-2-Deoxycytidine. New York, NY: PCH Publication; 1990. pp. 77–87.
15. Haas PS, Wijermans P, Verhoef G, Lubbert M. Treatment of myelodysplastic syndrome with a DNA methyltransferase inhibitor: lack of evidence for induction of chromosomal instability. Leuk Res. 2006;30:338–342. doi: 10.1016/j.leukres.2005.07.014. [PubMed] [Cross Ref]
16. Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia. 1997;11:S19–S23. doi: 10.1038/sj.leu.2400526. [PubMed] [Cross Ref]
17. Wijermans P, Lubbert M, Verhoef G, et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000;18:956–962. [PubMed]
18. Ben-Kasus T, Ben-Zvi Z, Marquez VE, Kelley J, Agbaria R. Metabolic activation of zebularine, a novel DNA methylation inhibitor, in human bladder carcinoma cells. Biochem Pharmacol. 2005;70:121–133. doi: 10.1016/j.bcp.2005.04.010. [PubMed] [Cross Ref]
19. Zhao M, Rudek MA, He P, et al. Quantification of 5-azacytidine in plasma by electrospray tandem mass spectrometry coupled with high-performance liquid chromatography. J. Chromatogr B Analyt Technol Biomed Life Sci. 2004;813:81–88. doi: 10.1016/j.jchromb.2004.09.012. [PubMed] [Cross Ref]
20. Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. J Pharm Sci. 1992;81:1–10. doi: 10.1002/jps.2600810102. [PubMed] [Cross Ref]
21. Wertz PW, Squier CA. Cellular and molecular basis of barrier function in oral epithelium. Crit Rev Ther Drug Carrier Syst. 1991;8:237–269. [PubMed]
22. Sugawara M, Kurosawa M, Sakai K, Kobayashi M, Iseki K, Miyazaki K. Ionic strength has a greater effect than does transmembrane electric potential difference on permeation of tryptamine and indoleacetic acid across Caco-2 cells. Biochim Biophys Acta. 2002;1564:149–155. doi: 10.1016/S0005-2736(02)00442-X. [PubMed] [Cross Ref]
23. Hoogstraate AJ, Senel S, Cullander C, Verhoef J, Junginger HE, Bodde HE. Effects of bile salts on transport rates and routes of FTIC-labelled compounds across porcine buccal epithelium in vitro. J Control Release. 2007;40:211–221. doi: 10.1016/0168-3659(95)00187-5. [Cross Ref]
24. Gandhi R, Robinson JR. Mechanisms of penetration enhancement for transbuccal delivery of salicylic acid. Int J Pharm. 1992;85:129–140. doi: 10.1016/0378-5173(92)90142-O. [Cross Ref]
25. Veuillez F, Kalia YN, Jacques Y, Deshusses J, Buri P. Factors and strategies for improving buccal absorption of peptides. Eur J Pharm Biopharm. 2001;51:93–109. doi: 10.1016/S0939-6411(00)00144-2. [PubMed] [Cross Ref]
26. Samrat M, Uday M. Chemistry and biology of bile acids. Curr Sci. 2004;87:1666–1683.
27. Nielsen HM, Rassing MR. TR 146 cells grown on filters as a model of human buccal epithelium, III: permeability enhancement by different pH values, different osmolality values, and bile salts. Int J Pharm. 1999;185:215–225. doi: 10.1016/S0378-5173(99)00165-9. [PubMed] [Cross Ref]
28. Xiang J, Fang X, Li X. Transbuccal delivery of 2′, 3′-dideoxycytidine: in vitro permeation study and histological investigation. Int J Pharm. 2002;231:57–66. doi: 10.1016/S0378-5173(01)00865-1. [PubMed] [Cross Ref]
29. Hoogstraate AJ, Coos Verhoef J, Pijpers A, et al. In vivo buccal delivery of the peptide drug buserelin with glycodeoxycholate as an absorption enhancer in pigs. Pharm Res. 2007;13:1233–1237. doi: 10.1023/A:1016024606221. [PubMed] [Cross Ref]
30. Hoogstraate AJ, Verhoef JC, Tuk B, et al. In-vivo buccal delivery of fluorescein isothiocyanate-dextran-4400 with glycodeoxycholate as an absorption enhancer in pigs. J Pharm Sci. 2007;85:457–460. doi: 10.1021/js950129k. [PubMed] [Cross Ref]
31. Senel S, Capan Y, Sargon MF. Enhancement of transbuccal permeation of morphine sulfate by sodium glycodeoxycholate in vitro. J Control Release. 1997;45:153–162. doi: 10.1016/S0168-3659(96)01568-4. [Cross Ref]
32. Senel S, Hoogstraate A, Spies F, Verhoef J, Bodde H. Enhancement of in vitro permeability of porcine buccal mucosa by bile salts: kinetic and histological studies. J Control Release. 1994;32:45–56. doi: 10.1016/0168-3659(94)90224-0. [Cross Ref]
33. Deneer VH, Drese GB, Roemele PE, et al. Buccal transport of flecainide and sotalol: effect of a bile salt and ionization state. Int J Pharm. 2002;241:127–134. doi: 10.1016/S0378-5173(02)00229-6. [PubMed] [Cross Ref]
34. Jasti BR, Zhou S, Mehta RC, Li X. Permeability of antisense oligonucleotide through porcine buccal mucosa. Int J Pharm. 2000;208:35–39. doi: 10.1016/S0378-5173(00)00543-3. [PubMed] [Cross Ref]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists