Sains Malaysiana 38(4)(2009): 601–607

Tc^99m-Sestamibi: Pembangunan Kit Radiofarmaseutikal untuk Pemetaan Jantung

(Tc99m-Sestamibi: Development of Radiopharmaceutical  Kit For Heart Imaging)

W.K. Wan Hamirul Bahrin, M.H. Zulkifli, T. Yahaya, A. Karuppaiya & A. Rasyieda

Bahagian Teknologi Perubatan, Agensi Nuklear Malaysia (Nuklear Malaysia)

Bangi, 43000 Kajang, Selangor, D.E., Malaysia

M.A. Mohd Cairul Iqbal* & H. Rosnani

Fakulti Farmasi, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd. Aziz, 50300 Kuala Lumpur, Malaysia

Received: 9 October 2008 / Accepted: 1 December 2008

ABSTRAK

Kajian untuk membangunkan dan membandingkan kit radiofarmaseutikal pemetaan jantung sestamibi Nuklear Malaysia (kit NM) dengan kit komersil dilaporkan. Tiga kelompok kit segera liofil B1, B2 and B3 dihasilkan secara pengeringan sejuk beku. Bagi tujuan perbandingan, kit komersil terdiri dari sestamibi Cardiolite, Polatom, ChiMIBI dan tetrofosmin Myoview. Ujian kawalan mutu yang dijalankan ialah ujian mikrobiologi, radiokimia dan kajian secara in vivo haiwan makmal. Ujian mikrobiologi mengesahkan kit NM adalah steril dan bebas pirogen. Ujian ketulenan radiokimia menggunakan kaedah kromatografi turus lapisan nipis segera (ITLC) dan kromatografi cecair berprestasi tinggi (HPLC) adalah melebihi 90% dan kekal stabil sehingga minggu ke-52. Kajian secara in vivo dilakukan ke atas tikus Sprague-Dawley pada selang masa 5, 30, 60, 120 and 1440 minit selepas suntikan dos. Peratus dos suntikan per gram jantung bagi Tc99m-B1 ialah 4.722±0.343%, 3.752±0.438%, 4.564±0.664%, 4.180±1.293% dan 1.090±0.230% pada selang masa 5, 30, 60, 120 dan 1440 minit masing-masing. Ini diikuti oleh Tc99m-B2 iaitu 3.852±0.406%, 3.628±0.425%, 3.366±0.316%, 4.324±1.044% dan 1.038±0.144%; Tc99m-B3 iaitu 5.404±0.351%, 4.818±0.579%, 6.015±0.774%, 5.028±1.353% dan 1.623±0.692%. Analisis statistik Independent T Test mendapati kesemua kit agen pemetaan jantung adalah signifikan bagi jantung berbanding ujian kawalan (P<0.05). Ini membuktikan penyerapan jantung adalah spesifik. Manakala analisis ke atas kit NM, mendapati nilai peratus dos suntikan per gram jantung berada pada nilai kit komersil. Penyingkiran Tc99m-sestamibi NM oleh darah, hati, ginjal dan usus kecil adalah cepat dan efisien. Penyebaran Tc99m-sestamibi NM dengan nisbah jantung terhadap paru-paru dan jantung terhadap hati menunjukkan potensi kit ini sesuai digunakan sebagai agen pemetaan jantung.

Kata kunci: kajian in vivo haiwan makmal; ketulenan radiokimia; radiofarmaseutikal; Tc99m-sestamibi

ABSTRACT

A development and comparison study of the Nuclear Malaysia’s Tc99m-sestamibi heart imaging agents (NM kits) and the commercial products is reported. Three batches of kits labelled as B1, B2 and B3 were produced by freeze drying technique. The commercial products such as sestamibi Cardiolite, Polatom, ChiMIBI and tetrofosmin Myoview were used in this study. The quality control testing which included microbiology testing, radiochemical and animal biodistribution study were conducted accordingly. The NM sestamibi kits passed the sterility and pirogen test. The Radiochemical Purity testing (RCP) was assessed by the Instant Thin Layer Chromatography (ITLC) and High-Performance Liquid Chromatography (HPLC) methods after the reconstitution of the Tc99m-sestamibi. The RCP results were above 90% and the kits were stable for 52 weeks. The animal biodistribution studies were carried out on Sprague-Dawley rats at 5, 30, 60, 120 and 1440 minutes post injection time intervals. The percentage injected dose per gram organ in heart for Tc99m-B1 were 4.722±0.343%, 3.752±0.438%, 4.564±0.664%, 4.180±1.293% and 1.090±0.230% at 5, 30, 60, 120 and 1440 minutes respectively. This is followed by the Tc99m-B2; 3.852±0.406%, 3.268±0.425%, 3.366±0.316%, 4.324±1.044% and 1.038±0.144%, Tc99m-B3; 5.404±0.351%, 4.818±0.579%, 6.015±0.774%, 5.028±1.353% and 1.623±0.692% at the same time intervals. Independent T Test showed that heart uptake was significant as compared to the control (p<0.05). The biodistribution study also showed that the radiopharmaceuticals localized selectively in the myocardium of rats. The NM sestamibi kits were comparable to the commercial products. Blood, lung, kidney and intestines washout were found to be fast and efficient. The biodistribution and analysis of heart-to-lung and heart-to-liver uptake ratios showed that NM sestamibi kits has a potential and could be used as heart imaging agents.

Keywords: Animal biodistribution study; radiopharmaceuticals; radiochemical purity; Tc99m-sestamibi

REFERENCES

Angela, L.L., Douglas, M.W., Douglas, W.M. & Hung, J.C. 2000. Evaluation of an alternative radiochemical purity testing method for technetium-99m-sestamibi. Journal Nuclear Medicine Technology 28: 259-263.

Bianco, J.A. & Wilson, M. 1998. Myocardial Imaging in Textbook in Nuclear Medicine. USA: Lippincott-Raven.

Bouquillon, S., Coulais, Y., Dartiguenave M., Tafani, J.A.M. & Guiraud, R. 1995. Synthesis, Characterization and Biodistribution of a New Technetium-99m Complex with Trimethylsilylmethylisonitrile. Comparison with 99mTc-TBI and 99mTc-MIBI. Nuclear Medical Biology 22(5): 585-588.

BP. 2007. British Pharmacopoeia. London: Her Majesty’s Stationary Office.

Cooper, M., Dustan, K. & Rotureau, L. 2006. The effect on radiochemical purity of modifications to the method of preparation and dilution of 99mTc-sestamibi. Nuclear Medicine Communications 27: 455-460.

Couriel, B. 1980. Freeze drying: post, present and future. Journal of Parenteral Drug Association 34: 352-357.

Decristoforo, C., Siller R., Chen, F. & Riccabona, G. 2000. Radiochemical purity of routinely prepared 99Tcm radiopharmaceuticals: A retrospective study. Nuclear Medicine Communications 21: 349-354.

Hoye, A. 1967. Determination of radiochemical purity of some radiochemicals and pharmaceuticals by paper chromatography, thin-layer chromatography and high voltage electrophoresis. Journal Chromatography 28: 379.

Hung, J.C., Wilson, M.E., Brown, M.L. & Gibbons, R.J. 1991. Rapid preparation and quality control method for technetium-99m-2-methoxy isobutyl isonitrile (technetium-99m-sestamibi). Journal Nuclear Medicine 32: 2162-2168.

Hung, J.C., Wilson, M.E., Gebhard, M.W. & Gibbons, R.J. 1995. Comparison of four alternative radiochemical purity testing methods for 99Tcm-sestamibi. Nuclear Medicine Communications 16: 99-104.

Jennings, T.A. 1999. Lyophilization: Introduction and Basic Principles. USA: Interpharma Press.

Kengo, H., Laurent, M.R., Yoshihiro, Y., Adriano, D., Ronaldo, L.L., Allen, R.G., Denny, D.W., George, A.B. & David, K.G. 2004. 99mTc-N-DBODC5, a New Myocardial Perfusion Imaging Agent with Rapid Liver Clearance: Comparison with 99mTc-Sestamibi and 99mTc-Tetrofosmin in Rats. Journal Nuclear Medicine 45: 2095-2101.

Kronauge, J.F., Kawamura, M., Lepisto, E., Holman, B.L., Davidson, A., Jones, A.G., Costello, C.E. & Zeng, C-H. 1990. Metabolic studies of the myocardial perfusion agent Tc-MIBI. In. Technetium and Rhenium in Chemistry and Nuclear Medicine. edited by Nicolini M., Bandoli G & Mazzi U. 3rd ed. pp. 677-681. Verona: Cortina International.

Michael, J.W. & Carol, S.R. 2003. Handbook of Radiopharmaceuticals Radiochemistry and Applications. USA: John Wiley & Sons Ltd.

Mohan, P., Samy, S., Shawkat, J. & Azu, O. 1995. A miniaturized rapid paper chromatography procedure for quality control of technetium-99m sestamibi. European Journal Nuclear Medicine 22: 1416-1419.

Narahara, K.A., Villanuevameyer, J., Thompson, C.J., Brizendine, M. & Mena, I. 1990. American Journal Cardiology 66: 1438.

Norenberg, J.P., Madhur, P.V., William, B.H., Dorothy, R.P., Jerry, L.B., Tamara, L.A. & Tomothy, R.C. 2005. The effect of selected preparation variables on the radiochemical purity of 99mTc-Sestamibi. Journal Nuclear Medicine Technology 33: 34-41.

Rakias, F. & Zolle, I. 2007. 99mTc-Labeled Myocardial Perfusion Agents. Dlm. Technetium-99m Pharmaceuticals Preparation and Quality Control in Nuclear Medicine, Zolle I. (pnyt.). hlm. 237-244. Austria: Springer Berlin Heidelberg.

Rey, L. & May, J.C. 2004. Freeze-Drying/Lyophilization of Pharmaceuticals and Biological Products. Ed. Ke-2. USA: Marcel Dekker Inc.

Richard, H., Lori, A.J., Thomas, E.K., Jamie, R.L., Tara, L.K., Mark, R.N. & John, J.S. 2004. A Better Method of Quality Control for 99mTc-Tetrofosmin. Journal Nuclear Medicine Technology 32: 72-78.

Ronald, B.W. & Coleman R.E. 2006. PET/CT Essentials for Clinical Practice. USA: Springer Science+Business Media, LCC.

Taillefer, R., Laflamme L., Dupras G., Picard M., Phaneuf D-C & Leveille J. 1988. Myocardial perfusion imaging with 99mTc-methoxy-isobutyl-isonitrile (MIBI): Comparison of short and long time intervals between rest and stress injections. Preliminary results. European Journal Nuclear Medicine 13: 515-522.

USP. 2000, The United States Pharmacopeia/USP24/NF19/2000. USA: Twinbrook Parkway.

Vertes, A. 2003. Handbook of Nuclear Chemistry, volume 4. Radiochemistry and Radiopharmaceutical Chemistry in Life Sciences. Netherlands: Kluwer Academic Publishers.

 Zaiton, Z. 2007. FSKB/2007/CAIRUL/10-JUL-2007-JUNE-2008. Surat kepada Jawatankuasa Etika Penggunaan Haiwan (UKMAEC). 28 Jun: 2.

Zolle, I. 2007. Technetium-99m Pharmaceuticals Preparation and Quality Control in Nuclear Medicine. Austria: Springer Science+Business Media.

*Corresponding author; email: mciamin@medic.ukm.my