Liquid Chromatography-Tandem Mass Spectrometry Methods for Determination of Delamanid in Mouse Plasma and Lung

Yukihiro Hirao^*, Toshihisa Koga, Noriyuki Koyama, Yoshihiko Shimokawa, Ken Umehara

Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima-shi, Japan.

DOI: 10.4236/ajac.2015.62009                

Abstract

Sensitive and selective liquid chromatography-tandem mass spectrometry methods have been developed and validated for the determination of delamanid in mouse plasma and lung. Sample preparation involved liquid-liquid extraction with diethyl ether for plasma, or protein precipitation followed by liquid-liquid extraction with tert-butyl methyl ether for lung homogenate. Chromatographic separation was performed on a reversed phase column with a linear gradient elution using purified water-formic acid (1000:2, v/v) and methanol-formic acid (1000:2, v/v) at a flow rate of 0.2 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometer using positive ion electrospray ionization in the selected reaction monitoring mode. The analytical methods were successfully validated for selectivity, calibration curve, accuracy, precision, extraction recovery, and stability over a range of 6 - 1000 ng/mL for plasma and 10 - 1000 ng/mL for lung homogenate. The validated methods were successfully applied for evaluation of pharmacokinetics of delamanid in male mice.

Keywords

Delamanid, LC-MS/MS, Mouse Plasma, Mouse Lung, Pharmacokinetics

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Diacon, A.H., Dawson, R., Hanekom, M., Narunsky, K., Venter, A., Hittel, N., Geiter, L.J., Wells, C.D., Paccaly, A.J. and Donald, P.R. (2011) Early Bactericidal Activity of Delamanid (OPC-67683) in Smear-Positive Pulmonary Tuberculosis Patients. International Journal of Tuberculosis & Lung Disease, 15, 949-954. http://dx.doi.org/10.5588/ijtld.10.0616
[2]	Gler, M.T., Skripconoka, V., Sanchez-Garavito, E., Xiao, H., Cabrera-Rivero, J.L., Vargas-Vasquez, D.E., Gao, M., Awad, M., Park, S.K., Shim, T.S., Suh, G.Y., Danilovits, M., Ogata, H., Kurve, A., Chang, J., Suzuki, K., Tupasi, T., Koh, W.J., Seaworth, B., Geiter, L.J. and Wells, C.D. (2012) Delamanid for Multidrug-Resistant Pulmonary Tuberculosis. The New England Journal of Medicine, 366, 2151-2160. http://dx.doi.org/10.1056/NEJMoa1112433
[3]	Skripconoka, V., Danilovits, M., Pehme, L., Tomson, T., Skenders, G., Kummik, T., Cirule, A., Leimane, V., Kurve, A., Levina, K., Geiter, L.J., Manissero, D. and Wells, C.D. (2013) Delamanid Improves Outcomes and Reduces Mortality in Multidrug-Resistant Tuberculosis. European Respiratory Journal, 41, 1393-1400. http://dx.doi.org/10.1183/09031936.00125812
[4]	Matsumoto, M., Hashizume, H., Tomishige, T., Kawasaki, M., Tsubouchi, H., Sasaki, H., Shimokawa, Y. and Komatsu, M. (2006) OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis in Vitro and in Mice. PLOS Medicine, 3, 2131-2144. http://dx.doi.org/10.1371/journal.pmed.0030466