MDR2 P-glycoprotein-mediated lipid secretion and its relevance to biliary drug transport

Frijters, C.M.G.; Groen, Albert K.; Elferink, Ronald P.J. Oude

doi:10.1016/s0169-409x(97)00499-7

Cited by 7 publications

(5 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[4][5][6][7][8] Recently, the role of mdr2 has been clarified in a series of in vivo and in vitro studies. [114][115][116][117][118][119] Smit et al have clarified the role of mdr2 as the flippase for phospholipids in studies involving disruption of mdr2. 115 In mutant mice, the biliary excretion of phosphatidylcholine (PC) was impaired, 115 and this in vivo finding was supported by examining the translocation of a fluorescent PC analogue (NBD-PC) in secretory vesicles (SV) isolated from murine mdr2 expressing yeast mutant sec6-4, a cell line whose unfused SV are accumulated intracellularly because there is no vesicular fusion pathway ( Figure 5).…”

Section: -2 Cooperative Role Of P-gp and P450 In The Detoxificationmentioning

confidence: 99%

The Role of P-Glycoprotein and Canalicular Multispecific Organic Anion Transporter in the Hepatobiliary Excretion of Drugs

Kusuhara

Suzuki

Sugiyama

1998

Journal of Pharmaceutical Sciences

109

View full text Add to dashboard Cite

Section: -2 Cooperative Role Of P-gp and P450 In The Detoxificationmentioning

confidence: 99%

The Role of P-Glycoprotein and Canalicular Multispecific Organic Anion Transporter in the Hepatobiliary Excretion of Drugs

Kusuhara

Suzuki

Sugiyama

1998

Journal of Pharmaceutical Sciences

109

View full text Add to dashboard Cite

“…This process involves the vectorial transport of compounds such as bile salts, phospholipids and cholesterol, as well as endobiotics and xenobiotics. This phenomenon requires P‐glycoprotein because it was assumed to be involved in the permeation of compounds across the plasma membrane (Frijters et al ., 1997). The biliary excretion of camptothecin was previously reported in an isolated perfused rat liver in vitro system (Platzer et al ., 2000).…”

Section: Discussionmentioning

confidence: 99%

“…This function has been demonstrated for excretion of xenobiotics via the canalicular membrane of hepatocytes into the bile (Hebert, 1997; Riley et al ., 2000). In addition, biliary elimination has been recognized not only to depend on bile salt secretion, but also to require the active participation of a protein, the P‐glycoprotein (Frijters et al ., 1997).…”

Section: Introductionmentioning

confidence: 99%

Effect of P‐glycoprotein modulators on the pharmacokinetics of camptothecin using microdialysis

Tsai

Lee²,

Yeh³

2001

British J Pharmacology

View full text Add to dashboard Cite

1 By performing microdialysis, this study investigated the pharmacokinetics of unbound camptothecin in rat blood, brain and bile in the presence of P-glycoprotein mediated transport modulators (cyclosporin A, berberine, quercetin, naringin and naringenin). Pharmacokinetic parameters of camptothecin were assessed using a non-compartmental model. 2 Camptothecin rapidly crosses the blood-brain barrier (BBB) within 20 min after camptothecin administration. The disposition of camptothecin in rat bile appeared to have a slow elimination phase and a peak concentration after 20 min of camptothecin administration. The area under the concentration versus time curve (AUC) for camptothecin in bile signi®cantly surpassed that in blood, suggesting active transport of hepatobiliary excretion. 3 In the presence of cyclosporin A camptothecin AUC, in the brain, was signi®cantly elevated but no signi®cant change in the presence of berberine, quercetin, naringin and naringenin. 4 With treatment by smaller doses of quercetin (0.1 mg kg 71 ), naringin (10 mg kg 71 ) and naringenin (10 mg kg 71 ), they signi®cantly diminished the camptothecin AUC in bile, but was not altered by the treatment of berberine (20 mg kg 71 ), a higher dose of quercetin (10 mg kg 71 ), and cyclosporin A treated (20 mg kg 71 ) and pretreated groups. 5 The distribution ratio (AUC bile /AUC blood ) of camptothecin in bile was decreased in the cyclosporin A, quercetin, naringin and naringenin treated groups. However, the distribution ratio in the brain was increased in the cyclosporin A groups, but was decreased in the groups treated with quercetin, naringin and naringenin. These results revealed that P-glycoprotein might modulate hepatobiliary excretion and BBB penetration of camptothecin.

show abstract

“…These observations have been combined in a hypothetical model describing the mechanism of lipid secretion (reviewed in refs. 3,4,16). In short, PC molecules are delivered to the canalicular membrane leaflet facing the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, biliary phospholipid secretion is controlled by the canalicular secretion of bile salts and by the activity of Mdr2 P-glycoprotein (Pgp). This ABC-transporter translocates phosphatidylcholine (PC) from the inner leaflet to the outer leaflet of the hepatocyte canalicular membrane, thereby supplying PC molecules for extraction by bile salts in the canalicular space (1)(2)(3)(4)(5). The gene products of murine Mdr1 a and Mdr1 b and human MDR1, have been identified as amphipathic drug export pumps.…”

mentioning

confidence: 99%

The role of different P-glycoproteins in hepatobiliary secretion of fluorescently labeled short-chain phospholipids

Frijters

Tuijn

Ottenhoff

et al. 1999

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

Class III P-glycoproteins (Pgps) mediate biliary phosphatidylcholine (PC) secretion. Recent findings that class I P-glycoproteins are able to transport several shortchain phospholipid analogues raises questions about the role of these Pgps in physiological lipid transport. We investigated the biliary secretion of C6-7-nitro-2,1,3-benzoxadiazol-4-yl (NBD)-labeled ceramide and its metabolites in Mdr1 a/ b and Mdr2 knockout mice compared to control mice. Biliary secretion of these NBD-lipids was unaffected in Mdr1 a/b ؊ / ؊ mice. Thus neither Mdr1a nor Mdr1b Pgp mediates biliary secretion of these lipids. In contrast, secretion of all three NBD-labeled short-chain phospholipids was significantly reduced in Mdr2 ؊ / ؊ mice. As in vitro studies revealed that Mdr2 Pgp is not able to translocate these lipid analogues, we hypothesized that Mdr2 ؊ / ؊ mice had a reduced PC content of the exoplasmic canalicular membrane leaflet so that extraction of the short-chain lipid probes from this membrane by canalicular bile salts was impaired. To investigate this possibility we studied the bile salt-mediated extraction of natural sphingomyelin (SM) and NBDlabeled short-chain SM from small unilamellar vesicles of different lipid composition. Natural SM could be extracted by the bile salt tauroursodeoxycholate from vesicles containing PC, cholesterol (CHOL), and SM (1:2:2) but not from vesicles containing only SM and CHOL (3:2). NBDlabeled short-chain SM could be extracted from vesicles containing PC while its extraction from pure SM:CHOL vesicles was reduced by 65%. These data confirm that the efficiency of NBD-SM extraction depends on the lipid composition and suggest that the canalicular membrane outer leaflet of Mdr2 ؊ / ؊ mice has a reduced PC content. -

show abstract

MDR2 P-glycoprotein-mediated lipid secretion and its relevance to biliary drug transport

Cited by 7 publications

References 75 publications

The Role of P-Glycoprotein and Canalicular Multispecific Organic Anion Transporter in the Hepatobiliary Excretion of Drugs

The Role of P-Glycoprotein and Canalicular Multispecific Organic Anion Transporter in the Hepatobiliary Excretion of Drugs

Effect of P‐glycoprotein modulators on the pharmacokinetics of camptothecin using microdialysis

The role of different P-glycoproteins in hepatobiliary secretion of fluorescently labeled short-chain phospholipids

Contact Info

Product

Resources

About