Development and validation of an ultra-performance liquid chromatography–tandem mass spectrometry method for quantification of SR1001, an inverse agonist of retinoid-related orphan receptors, and its application to pharmacokinetic studies in streptozotocin-induced diabetic mice

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Retinoic acid receptor-related orphan receptors (RORs) play critical roles in the onset and progression of type I diabetes, an autoimmune disease characterized by the destruction of pancreatic β-cells. SR1001, an ROR inverse agonist, has been proven to be an effective diabetes treatment in the non-obese diabetic (NOD) mouse model. However, optimization of this treatment is challenging because knowledge of SR1001 pharmacokinetic (PK) behaviors in type I diabetic animals is limited. The aim of our study was to develop and validate a specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC–MS/MS) method to measure the concentrations of SR1001 in plasma and biological samples. Using the developed UPLC–MS/MS method, SR1001 linearity ranges in biological matrices were determined to be 5–1000 ng/mL, with correlation coefficients of >0.99. The limit of detection (LOD) and limit of quantification (LOQ) values of SR1001 were 1 and 5 ng/mL, respectively. And the intra-day and inter-day variances were less than 10%, and accuracy was within 90%–110%. The extraction recoveries of SR1001 were ≥80%, and no significant matrix effect was observed. Using the validated UPLC–MS/MS method, levels of SR1001 in plasma and six major organs (heart, liver, spleen, lung, kidney, and brain) were determined in streptozotocin (STZ) −induced diabetic mice. The PK parameters of SR1001 were also calculated. The SR1001 drug concentration–time curves for organs and plasma showed similar trends, and the elimination half-lives of SR1001 in diabetic mice were about 12 h. SR1001 was highly bound to plasma protein, resulting in a much higher maximum concentration (Cmax = 144394 ng/mL) and area under the concentration–time curve (AUC0-t = 2728258 ng/mL*h), but a low tissue/plasma partition coefficient (Kp) value of <0.3.

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