Drug interaction evaluation of [99mTc]Tc-ketoconazole uptake with ketoconazole administration in Candidiasis mice model

Ahmad Kurniawan; Rizky Juwita  Sugiharti; Iim  Halimah; Iswahyudi Iswahyudi; Maula Eka Sriyani

doi:10.22146/ijp.899

Ahmad Kurniawan National Nuclear Energy Agency
Rizky Juwita Sugiharti Center for Applied Nuclear Science and Technology - National Nuclear Energy Agency Jalan Tamansari No.71 Bandung 40132
Iim Halimah Center for Applied Nuclear Science and Technology - National Nuclear Energy Agency Jalan Tamansari No.71 Bandung 40132
Iswahyudi Iswahyudi Center for Applied Nuclear Science and Technology - National Nuclear Energy Agency Jalan Tamansari No.71 Bandung 40132
Maula Eka Sriyani Center for Applied Nuclear Science and Technology - National Nuclear Energy Agency Jalan Tamansari No.71 Bandung 40132

Keywords: Drug interaction, Radiopharmaceuticals, [99mTc]Tc-ketoconazole, Candidiasis, Ketoconazole.

Abstract

The use of radiopharmaceuticals for infection detection has gained increasing attention for their application in nuclear medicine. The administration of [^99mTc]Tc-ketoconazole may altere pharmacological aspects including interaction data with some antifungals especially ketoconazole as a common drug for candidiasis treatment. The current study investigated the ex vivo biodistribution and pharmacokinetic interaction of [^99mTc]Tc-ketoconazole after ketoconazole administration in BALB/c mice. In this research,The [^99mTc]Tc-ketoconazole was prepared with radiochemical purity 94.59% (n=3). The ex vivo biodistribution uptake in infected muscle as a target organ showed 0.16±0.13%ID/g for control, 0.17±0.12 for 1 h, and 0.05±0.04 for 3 h after ketoconazole administration. The Target/Non-Target (T/NT) ratio between infected muscle compared with normal muscle showed 1.19±0.13 for the control group, 2.56±1.71 for 1 h and 0.86±0.67 for 3 h. The ex vivo biodistribution also showed high radioactivity uptake on the liver, lung, spleen and kidney. Pharmacokinetics analysis using PKSolver showed [^99mTc]Tc-ketoconazole half-life elimination (t1/2 beta) for the therapy group showed shorter elimination time 13.78±4.77 h compared with the control group 44.77±2.74 h after ketoconazole administration. Pharmacokinetics parameter change also occurred on the area under the curve of therapy group (AUC_0-inf) that is 26.10±18.97 %ID/g*h and maximum concentration (C_max) 13.05±9.48 %ID/g which was related with radiopharmaceutical absorption rate. This study proves that based on biodistribution and pharmacokinetics evaluation, the [^99mTc]Tc-ketoconazole application was recommended at 1 h post ketoconazole administration.

References

Alam, M. Z., Alam, Q., Fatani, A. J., Kamal, M. A., Abuzenadah, A. M., Chaudary, A. G., Haque, A. (2014). Candida identification : a journey from conventional to molecular methods in medical mycology. World Journal of Microbiology and Biotechnology, 30, 1437–1451. https://doi.org/10.1007/s11274-013-1574-z
Arendrup, M. C. (2010). Epidemiology of invasive candidiasis. Current Opnion in Critical Care, 16, 445–452. https://doi.org/10.1097/MCC.0b013e32833e84d2
Boerman, O. C., Rennen, H., Oyen, W. J. G., & Corstens, F. H. M. (2001). Radiopharmaceuticals to Image Infection and Inflammation. Seminars in Nuclear Medicine, XXXI(4), 286–295. https://doi.org/10.1053/snuc.2001.26189
Cutsem, J. V. A. N., Fransen, J., Gerven, F. VAN, & Janssen, P. A. J. (1985). Oral treatment with ketoconazole in systemic candidosis of guinea-pigs : microbiology , hematology and histopathology. Journal of Medical and Veterinary Micology, 23, 189–198.
Efficacy, S. A., Pletzer, D., Mansour, S. C., Wuerth, K., Rahanjam, N., & Hancock, R. E. W. (2017). New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host Microbe Interactions. American Society for Microbiology, 8(1), 1–16.
Garcia-cuesta, C., Sarrion Perez, M. G., & Bagán, J. V. (2014). Current treatment of oral candidiasis : A literature review. J Clin Exp Dent, 6(5), 576–582. https://doi.org/10.4317/jced.51798
Greenblatt, H. K., & Greenblatt, D. J. (2014). Liver Injury Associated With Ketoconazole : Review of the Published Evidence. The Journal of Clincial Pharmacology, 54(12), 1321–1329. https://doi.org/10.1002/jcph.400
IAEA. (2008). Technetium - 99m Radiopharmaceuticals Manufacture of kits (Technical reports Series No. 466). IAEA, (466).
Iii, W. B. H., Nigg, K. K., & Rhodes, B. A. (1982). Drug-Induced Changes in the Biologic Distribution of Radiopharmaceuticals. Seminars in Nuclear Medicine, XlI(2).
Jeanne Hawkins Van Tyle, P. . (1984). Ketoconazole Mechanism of Action, Spectrum of Activity, Pharmaco kinetics, Drug Interactions, Adverse Reactions and Therapeutic Use. Pharmacotherapy, 4(6), 343–373.
Kalista, K. F., Chen, L. K., Wahyuningsih, R., & Rumende, C. M. (2017). Clinical Characteristic and Prevalence of Invasive Candidiasis Patient in Cipto Mangunkusumo Hospital. Jurnal Penyakit Dalam Indonesia, 4(2), 56–61.
Lim, C. S., Rosli, R., Seow, H. F., & Chong, P. P. (2012). Candida and invasive candidiasis : back to basics. Eur J Clin Microbiol Infect Dis, 31, 21–31. https://doi.org/10.1007/s10096-011-1273-3
Olieveira, R. S., Smith, S. W., Maria, A., & Leao, A. C. (2008). Radiopharmaceuticals drug interactions : a critical review. Anais Da Academia Brasileira de Ciências, 80(4), 665–675.
Rizky Juwita Sugiharti, Iim Halimah, Isa Mahendra, M. eka. (2016). Biodistribusi Radiofarmaka 99mTc-Ketoconazol pada Infeksi yang Disebabkan oleh Candida albicans, Staphylococcus aureus dan Eschericia coli. Jurnal Sains Dan Teknologi Nuklir Indonesia, 17(2), 71–82.
Uno, J. U. N., Shigematsu, M. L., & Arai, T. (1982). Primary Site of Action of Ketoconazole on Candida albicans. Antimicrobial Agents and Chemoterapy, 21(6), 912–918.
Vallabhajosula, S., Killeen, R. P., & Osborne, J. R. (2010). Altered Biodistribution of Radiopharmaceuticals : Role of Radiochemical / Pharmaceutical Purity, Physiological, and Pharmacologic Factors. Seminars in Nuclear Medicine, 40(4), 220–241. https://doi.org/10.1053/j.semnuclmed.2010.02.004
Vorobyeva, A., Schulga, A., Rinne, S. S., Günther, T., Orlova, A., Deyev, S., & Tolmachev, V. (2019). Indirect Radioiodination of DARPin G3 Using N-succinimidyl- Para -Iodobenzoate Improves the Contrast of HER2 Molecular Imaging. International Journal of Molecular Sciences, 20(3047), 1–15.
W Becker and J Meller. (2001). The role of nuclear medicine in infection and inflammation. The Lancet, 1, 326–333.
Welling, M. M., Lupetti, A., Balter, H. S., Lanzzeri, S., Souto, B., Rey, A. M., … Nibbering, P. H. (2001). 99mTc-Labeled Antimicrobial Peptides for Detection of Bacterial and Candida albicans Infections. The Journal of Nuclear Medicine, 42(5), 788–795.
Zhang, Y., Huo, M., Zhou, J., & Xie, S. (2010). PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Computer Methods and Programs in Biomedicine, 99(3), 306–314. https://doi.org/10.1016/j.cmpb.2010.01.007
Zora, H., Muftuler, Z. F. B., Demir, I., Kilcar, Y., Iv, C. I., & Unak, P. (2012). Effect of a plant origin drug on the biodistribution of 99m Tc-DTPA in Wistar albino rats. Brazilian Journal of Pharmacognosy, 22(2), 344–349.