Impaired renal excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) sulfate in breast cancer resistance protein (BCRP1/ABCG2) knockout mice.

Abstract

Murine breast cancer resistance protein 1 (Bcrp1) is expressed in the brush-border membrane of proximal tubule cells of the kidney. The purpose of the present study is to investigate whether Bcrp1 could be involved in the urinary excretion of the human BCRP substrates, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole sulfate (E3040S) and 4-methylumbelliferone sulfate (4MUS), using Bcrp1(-/-) mice. E3040S and 4MUS were given to the mice by intravenous infusion, and plasma and kidney concentrations and the urinary excretion rate were determined. Knockout of Bcrp1 did not affect the creatinine clearance [7.17 +/- 1.00 and 8.66 +/- 2.02 ml/min/kg for Bcrp1(-/-) and wild-type mice, respectively]. The renal clearance of E3040S was 2.4-fold lower in Bcrp1 (-/-) mice compared with wild-type mice (2.74 +/- 0.41 versus 6.55 +/- 0.52 ml/min/kg). The concentration of E3040S in the kidney was increased in Bcrp1(-/-) mice compared with that in wild-type mice (55.5 +/- 10.5 versus 19.4 +/- 2.7 nmol/g kidney, respectively). In contrast, knockout of Bcrp1 did not affect the pharmacokinetic parameters of 4MUS, although 4MUS was predominantly excreted in the urine. This is to our knowledge the first demonstration of involvement of Bcrp1 in the renal secretion of organic sulfates. However, taking the results of 4MUS into consideration, the renal secretion of organic sulfates cannot be accounted for solely by Bcrp1, and transporters other than Bcrp1 are also involved.

• Authors: Naomi Mizuno, Michiko Suzuki, Hiroyuki Kusuhara, Hiroshi Suzuki, Kenji Takeuchi, Takuro Niwa, Johan W Jonker, Yuichi Sugiyama
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 32 Issue 9 Pg. 898-901 (Sep 2004) ISSN: 0090-9556 [Print] United States
• PMID: 15319327 (Publication Type: Comparative Study, Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcg2 protein, mouse
• Abcg2 protein, rat
• Benzothiazoles
• Membrane Proteins
• Pyridines
• Thiazoles
• E 3040
• Hymecromone

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (drug effects, genetics, metabolism)
• Animals
• Benzothiazoles
• Female
• Glomerular Filtration Rate (drug effects)
• Humans
• Hymecromone (administration & dosage, analogs & derivatives, pharmacokinetics, urine)
• Infusions, Intravenous
• Injections, Intravenous
• Kidney Tubules, Proximal (drug effects, pathology)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Pyridines (administration & dosage, pharmacokinetics, urine)
• Species Specificity
• Thiazoles (administration & dosage, pharmacokinetics, urine)