Bioavailability, plasma protein binding and metabolic stability studies of a ALDH2 activator, alda-1, using a validated LC-ESI-MS/MS method in rat plasma

Abstract

Alda-1 is an activator of the enzyme ALDH2. It has been suggested as a novel therapeutic for cardiovascular implications such as myocardial infarction, coronary bypass surgery, heart transplantation, peripheral artery disease, ischemia reperfusion injury, angina and alcoholic cardiomyopathy. Despite its widespread experimental use, no reports are available on its pharmacokinetics or bioanalytical quantification. In the present study, a simple, precise and reliable LC-ESI-MS/MS method has been developed and validated for the first time for quantification of alda-1 in plasma. Alda-1 was analyzed on a C18 column using methanol and 0.1% formic acid (60 : 40, v/v) as the mobile phase at a flow rate of 0.7 mL min⁻¹. The method was found to be linear within the concentration range of 1–500 ng mL⁻¹. The intra- and inter-day precision and accuracy were within acceptable limits. For the first time, the preclinical oral and intravenous pharmacokinetics of alda-1 were conducted. Alda-1 was found to be a rapidly absorbed, high clearance and poorly bioavailable compound in rats. Its plasma protein binding was found to be 82–86%. In view of the new regulatory guidelines, incurred sample reanalysis was also performed and all the samples were found within 15% of the mean value. From the in vitro microsomal incubation studies, it was found to be a high extraction compound. The data presented here provide important information to support the in vivo efficacy of alda-1 and would be helpful in its further development as a therapeutic agent and synthesis of its analogs with better systemic exposure and disposition properties.