Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Abstract

The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

Development and validation of an LC‐MS/MS method for the determination of a novel thienoquinolin urea transporter inhibitor PU‐48 in rat plasma and its application to a pharmacokinetic study

“…In the present study, a simple, specific and sensitive LC‐MS/MS method was developed for quantitative determination of PU‐48 in rat plasma. Under the HPLC preliminary experiment conditions, several compounds were tested for the internal standard (IS), including several thienoquinolin analogs and megestrol acetate (Li et al, ; Lu et al, ). Because the chromatographic peaks of both PU‐48 and megestrol acetate at 293 nm ultraviolet (UV) wavelength showed less interference from endogenous substances in plasma (see Supporting Information, Appendix Figure S1), megestrol acetate was chosen as the IS for its appropriate UV–vis absorption by both UV (HPLC) and PDA detectors (LC‐MS/MS), retention time and high extraction recovery.…”

<p>Self-Microemulsifying Drug Delivery System for Improved Oral Delivery and Hypnotic Efficacy of Ferulic Acid</p>

“…26,27 SMEDDS decreases the elimination and clearance of drugs by altering their distribution in tissues. 28,29 Thus, we speculated that SMEDDS may be an effective carrier to improve the pharmacokinetic behavior and anti-insomnia efficacy of FA. In this study, we aimed to 1) prepare SMEDDS as a carrier of FA, 2) characterize it on the basis of its morphology, droplet size, and in vitro release of FA, and 3) examine its impact on the disposition of FA in vivo in terms of its oral bioavailability and tissue distribution in rats and on the hypnotic efficacy of FA in insomnia mice.…”