Pharmacokinetics, Bioavailability, and Tissue Distribution of the Kirsten Rat Sarcoma Inhibitor Adagrasib in Rats Using UPLC-MS/MS.
Drug Des Devel Ther
; 18: 1-12, 2024.
Article
en En
| MEDLINE
| ID: mdl-38205395
ABSTRACT
Purpose:
Adagrasib is a selective and reversible inhibitor of KRAS G12C, which significantly delays the progression of solid tumors. However, the absorption, distribution, metabolism, and excretion of adagrasib in vivo are unclear. This study explores the absorption and distribution of adagrasib in vivo.Methods:
An ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method was established for the determination of adagrasib in the rat plasma and tissue. Sprague-Dawley rats were intravenous administrated (5 mg/kg) and oral administrated (30 mg/kg) with adagrasib, and the plasma concentration of adagrasib was determined. After single oral administration of adagrasib (30 mg/kg), the heart, liver, spleen, lung, kidney, intestine, and pancreas were excised. The organs were homogenized with saline solution, and the concentration of adagrasib in tissues was determined.Results:
The intra- and inter-day accuracy were from 84.90% to 113.47%, and the precision was within ±15%. The matrix effect and recovery were within ±15%. The maximum plasma concentration (Cmax) of adagrasib was 677.45 ± 58.72 ng/mL. The elimination half-life time (t1/2) was 3.50 ± 0.21 h after oral administration and 2.08 ± 0.54 h after intravenous administration. The oral bioavailability was 50.72%. The highest concentrations of adagrasib in liver was 5047.80 ± 676.48 ng/g at 2 h after administration, and it was still detectable at 24 hours after administration.Conclusion:
Adagrasib was slowly absorbed and cleared rapidly, and it was also widely distributed in vivo. This study provides a potential reference for adagrasib in clinical studies.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Acetonitrilos
/
Piperazinas
/
Pirimidinas
/
Proteínas Proto-Oncogénicas p21(ras)
/
Cromatografía Líquida con Espectrometría de Masas
Idioma:
En
Revista:
Drug Des Devel Ther
Asunto de la revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Año:
2024
Tipo del documento:
Article