Preclinical pharmacokinetics, tissue distribution and excretion studies of a novel anti-candidal agent-thiosemicarbazide derivative of isoniazid (TSC-INH) by validated UPLC–MS/MS assay

Journal Article

Al-Rashood, Muzaffar Iqbala, Essam Ezzeldin, Mashooq A. Bhat, Mohammad Raish, Khalid A. . 2016

• Magazine \ Newspaper: Journal of Pharmaceutical and Biomedical Analysis
• Volume Number: 117
• Pages: 109-117

Publication Abstract

A simple and sensitive UPLC–MS/MS assay was developed and validated for rapid determination of
thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues,
urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as
an internal standard (IS). Chromatographic separation was achieved on Acquity BEHTM C18 (50×2.1mm,
1.7mm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid)
at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH
and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the
acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study
showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was
rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral
dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels
in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier.
Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying
that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo
pharmacokinetics and disposition properties, this study will be beneficial for further development of
compound TSC-INH in future studies.