Elucidation of pharmacokinetics of novel DNA ligase I inhibitor, S012-1332 in rats: Integration of in vitro and in vivo findings

Publication date: Available online 18 September 2018Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Riyazuddin Mohammed, R. Valicherla Guru, Husain Athar, Kamil Hussain Mohd, Shukla Minakshi, Katekar Roshan, P. Gupta Anand, Singh Pragati, Banerjee Dibyendu, Hajela Kanchan, R. Gayen JiaurAbstractS012-1332 is the first DNA ligase I inhibitor that demonstrated in vivo anti-breast cancer activity. The present study aimed to assess the in vivo pharmacokinetics of S012-1332 in rats and interpret them with in vitro findings. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S012-1332. Following oral administration, the absolute bioavailability was 7.04 %. The absorption was prolonged which can be explained by low solubility in simulated gastric fluid and several folds higher solubility in simulated intestinal fluid. The effective permeability across the intestinal membrane in in situ single pass perfusion study for S012-1332 was 5.58 ± 1.83 * 10-5 cm/sec compared to 5.99 ± 0.65 * 10-5 cm/sec for carbamazepine, with no significant difference, indicating S012-1332 has high permeability. It was rapidly partitioning into plasma in blood, where it was stable. Plasma protein binding was moderate which may have attributed to the rapid distribution out of the vascular compartment. The pharmacokinetics of S012-1332 was characterized by extensive clearance as seen with rat liver ...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research