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, 2. M Iqbal, E Ezzeldin, M A Bhat, M Raish, K A . 2016

• Magazine \ Newspaper: Journal of Pharmaceutical and Biomedical Analysis,
• Volume Number: 17
• Pages: 109-117

Publication Abstract

tA simple and sensitive UPLC–MS/MS assay was developed and validated for rapid determination ofthiosemicarbazide 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 asan internal standard (IS). Chromatographic separation was achieved on Acquity BEHTMC18(50 × 2.1 mm,1.7 m) 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-INHand m/z 380.08 → 316.03 for IS in ESI negative mode. All validation parameter results were within theacceptable range described in guideline for bioanalytical method validation. The pharmacokinetic studyshowed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It wasrapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oraldose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest lev-els 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 implyingthat TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivopharmacokinetics and disposition properties, this study will be beneficial for further development ofcompound TSC-INH in future studies.