Involvement of Multidrug Resistance-Associated Protein 2 (Abcc2) in Molecular Weight-Dependent Biliary Excretion of β-Lactam Antibiotics

Abstract

ABSTRACT:In the present study, we attempted to identify the membrane permeation process(es) primarily involved in the molecular-weightdependent biliary excretion of ␤-lactam antibiotics. A search of the literature indicated that the molecular weight threshold operates mainly in the transport process across bile canalicular membranes. We confirmed that biliary clearance of the model biliaryexcretion-type cephalosporin cefoperazone was reduced to 10% of the control in Eisai hyperbilirubinemic rats, which are genetically deficient in multidrug resistance-associated protein (Mrp) 2, indicating that Mrp2 plays a major role as an efflux transporter on the canalicular membranes. ATP-dependent uptake of several cephalosporins including cefoperazone, cefbuperazone, cefpiramide, and ceftriaxone, all of which are mainly excreted into bile, was confirmed in membrane vesicles from Sf9 cells transfected with rat Mrp2. Both the inhibitory potency of the cephalosporins for Mrp2-mediated transport and the uptake of cephalosporins by Mrp2-expressing vesicles were molecular weight-dependent, suggesting that Mrp2 is one of the major transporters involved in molecular weight-dependent biliary excretion. An uptake study in membrane vesicles of Sf9 cells transfected with breast cancer resistance protein (Bcrp) revealed that Bcrp accepts cefoperazone, cefbuperazone, cefpiramide, cefotetan, ceftriaxone, cefotiam, cefamandole, and cefazolin as substrates, and Bcrp-mediated transport was also molecular weight-dependent, suggesting that Bcrp also contributes to molecular weight-dependent biliary excretion of ␤-lactam antibiotics in rats.

Quantitative Time-Lapse Imaging-Based Analysis of Drug-Drug Interaction Mediated by Hepatobiliary Transporter, Multidrug Resistance-Associated Protein 2, in Sandwich-Cultured Rat Hepatocytes

“…In the current study, we used membrane vesicles prepared from insect Sf9 cells expressing ABC transporters. Because we have shown that Mrp2 transport activity in the same system corresponded well with its in vivo function (Kato et al, 2008), it was thought that these results reflect physiological function of these transports. Indeed, results obtained from Bcrp-expressing vesicles are consistent with the findings in Bcrp(Ϫ/Ϫ) mice (Nezasa et al, 2006).…”

“…MRP2 plays an essential role in regulation of the serum bilirubin level by eliminating its conjugate from the liver, because a genetic defect of MRP2 in humans leads to familial conjugated hyperbilirubinemia, known as Dubin-Johnson syndrome (Kartenbeck et al, 1996;Paulusma et al, 1997). In addition, MRP2 mediates efflux transport into bile of many structurally diverse xenobiotics and anticancer drugs in either intact or conjugated forms (Kato et al, 2008). We have shown that MRP2 plays an important role in the hepatobiliary secretion of drugs by using SCRHs (Fukuda et al, 2008(Fukuda et al, , 2010.…”

In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

“…Because Bcrp protein expression increased during culture, in contrast to the decrease in Mrp2 and bile salt export pump expression (Li et al, 2010), intrinsic biliary clearance for rosuvastatin is relatively higher than that of other compounds in SCRH. Meanwhile, it was reported that Mrp2 mainly contributes to biliary secretion of pravastatin, angiotensin receptor blockers (valsartan and olmesartan), and ␤-lactam antibiotics (cefoperazone and cefpiramide) (Muraoka et al, 1995;Sasaki et al, 2004;Takayanagi et al, 2005;Yamashiro et al, 2006;Kato et al, 2008). Because the main contributor that excreted rosuvastatin into bile was different from that for the other compounds, a deviation of rosuvastatin from the correlation among these compounds would be observed.…”

“…Because the main contributor that excreted rosuvastatin into bile was different from that for the other compounds, a deviation of rosuvastatin from the correlation among these compounds would be observed. Meanwhile, it was reported that cefmetazole was not a substrate of Mrp2 and Bcrp (Kato et al, 2008). Although the primary transporter for biliary excretion of cefmetazole is unknown, it may be possible that the activity change of the main contributors for biliary excretion of cefmetazole caused the deviation of cefmetazole from the correlation.…”

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

“…However, the reasons behind the molecular mass threshold are not well understood. Kato et al (2008) studied the substrate affinity of the cephalosporins for MRP2 and BCRP and suggested involvement of efflux pumps in molecular mass-dependent BE of ␤-lactam antibiotics in rats. Because of the broad substrate specificity of the canalicular efflux transporters [P-glycoprotein (P-gp), BCRP, and MRP2], we hypothesized that substrate specificity of sinusoidal uptake transporters, particularly OATPs, defines the molecular mass threshold and the general physicochemical space of BE.…”