4.6 Article

Quantitative Determination of 5-Aminoisoquinoline, a PARP-1 Inhibitor by UPLC-MS/MS: In Silico ADME Profile and In Vitro Metabolic Stability Study

Journal

APPLIED SCIENCES-BASEL
Volume 12, Issue 12, Pages -

Publisher

MDPI
DOI: 10.3390/app12125998

Keywords

5-Aminoisoquinoline; UPLC-MS; MS; metabolic stability; microsomes

Funding

  1. King Saud University, Riyadh, Saudi Arabia [RSP-2021/353]

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A simple, selective and reliable ultra-performance liquid chromatography-tandem mass spectrometry assay has been developed for the quantitative analysis of 5-Aminoisoquinoline (5-AIQ) in plasma. The assay was linear in the concentration range of 1.0 to 666 ng/mL and showed good precision and bias. In silico ADME prediction showed that 5-AIQ is very soluble in water and has high gastrointestinal absorption and blood-brain barrier permeability. The validated method can be utilized for future pharmacokinetic and bio-distribution studies.
5-Aminoisoquinoline (5-AIQ) is a water-soluble, potent and selective Poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor, widely used as a biochemical and pharmacological tool to study the inhibitory effect of PARPs enzyme. In this study, a simple, selective and reliable ultra-performance liquid chromatography-tandem mass spectrometry assay has been developed for the quantitative analysis of 5-AIQ in plasma using pantoprazole as an internal standard (IS). Both 5-AIQ and IS were separated on an Acquity CSH18 (2.1 x 100 mm; 1.7 mu m) column after chromatographic elution of mobile phase comprising of 10 mM ammonium acetate and acetonitrile (35:65; v/v) at a flow rate of 0.3 mL/min. Electrospray ionization in positive mode was used for sample ionization and precursor to product ion transitions of 145.0 > 91.0; 145.0 > 117.4 for 5-AIQ and 384.0 > 138.1 for IS were used for detection and quantification in multiple reaction monitoring mode. The assay was linear in the concentration range of 1.0 to 666 ng/mL with correlation coefficient of >= 0.995. The precision and bias were within the acceptable limits of <= 12.68% and -8.6 to 5.9%, respectively, with mean recovery of 79.1% from plasma and negligible matrix effects (92.4%). In silico ADME prediction, 5-AIQ showed to be very soluble in water and high gastrointestinal absorption along with blood-brain barrier (BBB) permeability. The validated assay was successfully applied in a metabolic stability study, and 5-AIQ was moderately metabolized by human liver microsomes with an in vitro half-life of 14.5 min and intrinsic clearance of 47.6 mu L/min/mg. The validated method can be utilized for future pharmacokinetic and bio-distribution studies.

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