Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension

Abstract

Background Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination. Methods The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. Results Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. Conclusions Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

“…Briefly, CYP3A4 is an enzyme responsible for over 50% of drug metabolism in humans; it functions as a xenobiotic expelling enzyme found in the liver. Studies have linked CYP3A4 overexpression to multidrug resistance in several diseased states such as cancer . Hence, its inhibition is a common practice in drug and pharmaceutical design.…”

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…CYP3A4 is responsible for 40%–45% of all phase I metabolism and accounts for up to 70% of gastrointestinal CYP activity. For example, the Octreotide oral bioavaibility was decreased due to over expression of P‐gp and CYP3A4, by which increased the intestinal fierst pass effect on Octreotide and limiting its anti‐hypertensive effect (Sun et al, 2021). Ketoconazole inhibited the CYP 3A4 based metabolism of Erythromycin (Lewis & Dickins, 2002).…”

“…CYP3A4 and P‐gp are co‐expressed in the intestine, which can synergistically regulate intestinal transporters and drug metabolism; finally, limit the oral bioavailability of the drug because both have the almost same substrate specificity and may also be responsible for the drug–drug interaction (Zhang, Dong, et al, 2021; Sun et al, 2021; Schaffenburg et al, 2021; Thummel, 2007). The total amount of intestinal CYP3A4 content averages about 40% of the liver content.…”

Global Analysis of Models for Predicting Human Absorption: QSAR, In Vitro, and Preclinical Models

“…Rat-specific uptake transporter analogues critical for absorption like Oatp2b1 show up to 77% amino acid sequence similarity with human OATP2B1 32 and, in some cases, can show similar substrate affinities. 33,34 Efflux transporters (like Pgp and MRP2), responsible for intestinal efflux and reduced absorption, 35 have very similar binding site residue overlap 36 and gene expression 37 for humans and rodents. Many predictions for substrates of these transporters fell within 2- fold of observed (Supporting Information Figure S12).…”