Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

Abstract

The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses. The potential effects of the inhibitor administration on PVP were also examined. The results suggest that P-gp, MRP2 and CYP3A4 play important roles in prohibiting the enteral absorption of OCT, particularly under a PH environment. Moreover, inhibitors of P-gp, MRP2 and CYP3A4 decrease the first-pass effects of OCT and effectively reduce PVP under PH conditions. Therefore, the present results suggest P-gp, MRP2 and CYP3A4 are key factors in the intestinal absorption of OCT. The inhibition of P-gp, MRP2 and CYP3A4 can markedly decrease the first-pass effects of OCT, and their use may facilitate the use of orally administered OCT.

Keywords: P-glycoprotein; absorption; cytochrome P450 3A4; multidrug resistance-associated protein 2; octreotide.

Figure 1.

Chemical structure of octreotide.

Figure 2.

mRNA and protein expression levels of P-gp/MRP2/CYP3A4 in the intestinal mucosa of rats with or without PH. Data are expressed as the means ± standard deviation (n=4). A two-tailed unpaired t-test was used to assess significant differences. (A) Reverse transcription-polymerase chain reaction data showing the CYP3A1, MDR1 (mdr1a, mdr1b) and MRP2 expression levels in the rat intestine in each group. (B) Western blot data showing the CYP3A4, P-gp and MRP2 protein expression levels in the rat intestine in each group. (C) Immunohistochemistry showing the location and extent of CYP3A4, P-gp and MRP2 protein expression in the rat intestine in each group (magnification, ×100). *P<0.05, Group N + OCT vs. Group N. **P<0.05, Group PH + OCT vs. Group PH; ^$P<0.05, Group PH vs. Group N; ^#P<0.01, Group PH + OCT + I vs. each other group. N, normal control; OCT, octreotide; PH, portal hypertension; I, inhibitors; cyp3a1, cytochrome P450 3A1; MRP2, multidrug-resistence associated protein 2; P-gp, P-glycoprotein.