Effects of Probucol Formulations on Mesenteric Lymphatic Trans-port Efficiency and Pharmacokinetics in Rats

Abstract

ObjectiveTo compare the effects of probucol olive oil and suspension formulations on the pharmacokinetics and mesenteric lymphatic transport in rats using an innovative mesenteric-jugular lymphatic duct assisted reflux model.MethodsTwelve Sprague-Dawley (SD) rats were randomly divided into four groups: suspension preparation-jugular vein single cannulation group (H-JD group), suspension preparation-jugular vein and intestinal lymphatic double cannulation group (H-JCS group), olive oil preparation-jugular vein single cannulation group (G-JD group), olive oil preparation-jugular vein and intestinal lymphatic double cannulation group (G-JCS group). The concentrations of probucol in whole blood and lymph fluid of rats at different times were determined by liquid chromatography and tandem mass spectrometry (LC-MS/MS), and drug-time curves were drawn. The pharmacokinetic parameters, relativebioavailability (Frel) and percentage dose in lymph fluid were calculated.ResultsThe drug-time curve of each group conformed to the non-compartmental model. The peak times (Tmax) of the H-JD group, H-JCS group, G-JD group, and G-JCS group were (11±12), (5±2), (13±9), and (19±9) h, respectively; the peak concentrations (Cmax) were (148±60), (207±137), (453±204), and (309±177) ng/mL, respectively; the areas under the curve (AUClast) were (3 210±885), (3 677±2 014), (12 360±6 629), and (8 080±3 064) h·ng·mL-1, respectively. The percentages of lymphatic fluid dose in the H-JCS and G-JCS groups were (1.29±0.50)% and (2.59±0.43)%. Compared with the H-JD group, the Frel of probucol in the G-JD group was (409±269)%; compared with the H-JCS group, the Frel of probucol in the G-JCS group was (309±256)%. Compared with the H-JD and H-JCS groups, the whole blood values of Cmax, Tmax, AUClast and percentage of lymphatic fluid probucol concentrations of the G-JD and the G-JCS groups were significantly increased (P＜0.05). The AUClast of whole blood in the G-JD group was significantly higher than that in the G-JCS group (P＜0.05), but there was no significant difference between the H-JD and H-JCS groups (P > 0.05).ConclusionOlive oil formulation can improve the ratio of probucol transport through mesenteric lymph as well as its bioavailability.

Keywords

• probucol
• mesenteric lymph fluid
• pharmacokinetics
• transport
• sprague-dawley rats