Multidrug Resistance Reversal Activity of Some New Dihydropyridines Studied by IN SITU Single-Pass Intestinal Perfusion (SPIP) Method in Rat

Аннотация

P-glycoprotein (P-gp) mediated efflux affects the pharmacokinetics of several drugs. By analogy to verapamil, 1,4-dihydropyridines (DHPs) have been widely studied as P-gp inhibitors. Previously, we have reported on two new DHPs: IA₁(A) and IIA₅(B) as inhibitors of human MRP1, an efflux protein closely related to P-gp. The aim of the present study was to investigate the inhibitory effects of these two compounds on intestinal P-gp using the method of in situ single-pass intestinal perfusion (SPIP) in rat. According to this, the intestinal absorption of zidovudine (a P-gp substrate) was studied in anaesthetized rat jejunum in the absence and presence of DHPs IA₁(A) and IIA₅(B) (2 mg/kg). Verapamil (0.8 mg/kg), a well-known P-gp inhibitor, was employed as a standard. Zidovudine solution (200 ig/mL) in phosphate buffer (pH 7.4) was perfused through the jejunal segment, the perfusate concentrations were quantified by HPLC, and the permeability coefficient (P_eff) and fraction absorbed (F_abs) were calculated. Phenol red was used as a non-absorbable marker to correct water flux through the segment. In rats pretreated with compounds IA₁ and IIA₅, P_eff and F_abs of zidovudine were found to be 0.1669 ± 0.12 cm/sec, 0.2035 ± 0.18 and 0.2798 ± 0.12 cm/sec, 0.3015 ± 0.14, respectively, and were comparable to those of the standard (P_eff = 0.462713 ± 0.3 cm/sec, F_abs = 0.511835 ± 0.14). The differences between IA₁, IIA₅ and the standard were evaluated using ANOVA and found to be statistically significant (P < 0.05). Compounds IA₁ and IIA₅ have a modulating effect on intestinal P-gp. Compound IIA₅ was relatively more potent P-gp inhibitor and, quite interestingly, the results were in agreement with our earlier in silico and in vitro studies.