Differential effects of liver steatosis on pharmacokinetic profile of two closely related hepatoselective NO-donors; V-PYRRO/NO and V-PROLI/NO

Purpose to analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective no-donors – v-pyrro/no and v-proli/no. methods c57bl/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (hfd mice). pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of v-pyrro/no and v-proli/no (0.03 mmol/kg). hepatic clearance was evaluated ex vivo in the isolated perfused mice liver and in vitro with the use of liver microsomes. results v-pyrro/no and v-proli/no,despite similar structure,displayed different pharmacokinetic properties. v-pyrro/no was uptaken and metabolized by the liver,while v-proli/no was eliminated unchanged with urine. in hfd mice,despite increased cyp450 metabolism of v-pyrro/no the elimination rate was slower most likely due to the impairment of hepatic microcirculation caused by liver fat accumulation. in turn,in hfd mice renal clearence of v-proli/no was accelerated and volume of distribution was increased most likely due to additional intracellular water in hfd mice. conclusions the pharmacokinetics of v-proli/no,the novel proline-based analog of v-pyrro/no with additional single carboxylic acid moiety,attached to the molecule of v-pyrro/no to improve the water solubility,was differently affected by liver steatosis and obesity as compared with the parent compound v-pyrro/no. © 2017 institute of pharmacology,polish academy of sciences