P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

Abstract

Purpose: Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.Experimental Design: Abcb1a/1b, Abcc3 -/-, Abcb1a/1b;Abcc2 -/-, and Abcc2;Abcc3 -/-mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.Results: P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2 -/-mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3 -/-mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.Conclusions: P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide. Clin Cancer Res; 16(1); 130-40. ©2010 AACR.

Role of drug transporters: an overview based on knockout animal model studies

“…Co-operative action of Mrp2 and Mrp3 was demonstrated using Mrp2 and Mrp3 double knockout mouse. The hepatobiliary disposition of fexofenadine and the pharmacokinetics of etoposide and/or etoposide glucuronide were greatly altered in this double knockout mouse model (Tian et al 2008;Lagas et al 2010). Mrp4 may also be involved in the hepatic basolateral excretion of sulfate conjugates (Zamek-Gliszczynski et al 2006a).…”

“…Like Bcrp, Mrp1 may contribute to the efflux at the BBB in synergism with P-gp (Wijnholds et al 2000a;Johnson et al 2001). Compared to wild type mice, Mrp4 knockout mice showed elevated brain and CSF concentration of topotecan (Lagas et al 2010). Mrp4 may be also a component of defense mechanism of BBB as an efflux system for nucleoside-based analogues (Belinsky et al 2007).…”

“…Mrp2/3 (Abcc2/3) Contribution to the hepatobiliary disposition of fexofenadine (Tian et al 2008) Modulating the pharmacokinetics of etoposide and/or etoposide glucuronide (Lagas et al 2010) Bcrp (Abcg2) Reducing risk for developing protoporphyria and diet-dependent phototoxicity (Jonker et al 2002) Effects on oral bioavailability and tissue distribution of phytoestrogens (Enokizono et al 2007) Inhibitory effect on intestinal efflux of sulfasalazine by curcumin (Shukla et al 2009) Modulating the oral absorption and biliary excretion of various substrates including nitrofurantoin, sulfasalazine and compound A Role of drug transporters P-gp has been indicated in the pharmacokinetics of etoposide and/or etoposide glucuronide through triple knockout mouse models of Mrp2/Mdr1a/1b (Lagas et al 2010). Bcrp may lower oral bioavailability by working as an efflux pump on the apical side of the intestine, as evident from increased bioavailability of genistein, daidzein, and sulfasalazine observed in Bcrp knockout mice (Zaher et al 2006;Alvarez et al 2011;Yang et al 2012).…”

The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients

“…One important chemotherapeutic drug, etoposide (VP-16) is poorly absorbed from the gastrointestinal tract (GI) following oral administration, leading to a reduction in clinical outcomes [1]. This drug is dynamically pumped out from the intestinal wall by a transmembrane permeability glycoprotein (P-gp) and metabolized by cytochrome P450, mainly cytochrome P450 3A4 that affects its pharmacokinetic parameters [2]. The unfavorable physicochemical properties of VP-16 along with adverse physiological barrier of the GI tract constitute major challenges for successful oral delivery.…”

Dose-Dependent Disposition of Methotrexate in Abcc2 and Abcc3 Gene Knockout Murine Models

“…The use of established in vitro permeability and in situ/ex vivo models, such as perfused organ models (Xia et al, 2007), provides useful yet isolated information as to the potential impact of transporters on drug disposition. Given that drugs may be substrates for multiple transporters of overlapping function (Vlaming et al, 2009a;Lagas et al, 2010a), whole-body animal models are required to provide a comprehensive analysis of the PKs of a drug. In this regard, the use of gene knockout animal models provides an opportunity to characterize not only how specific transporters impact drug disposition, but they also may be used as a tool to examine how specific inhibitors influence drug disposition (Sikic et al, 1997).…”