Characteristics of pemetrexed transport by renal basolateral organic anion transporter hOAT3.

Article Details

Citation

Kurata T, Iwamoto T, Kawahara Y, Okuda M

Characteristics of pemetrexed transport by renal basolateral organic anion transporter hOAT3.

Drug Metab Pharmacokinet. 2014;29(2):148-53. doi: 10.2133/dmpk.dmpk-13-rg-042. Epub 2013 Sep 17.

PubMed ID
24042472 [ View in PubMed
]
Abstract

PURPOSE: Pemetrexed transport by human organic anion transporters, hOAT1 (SLC22A6) and hOAT3 (SLC22A8), were characterized in comparison with methotrexate. METHODS: Accumulation of pemetrexed and methotrexate in hOAT1- and hOAT3-expressing cells were evaluated. Pemetrexed and methotrexate were determined by HPLC. Kinetic parameters were calculated by Eadie-Hofstee plot. RESULTS: When HEK-hOAT3 and -hOAT1 cells were incubated with 100 microM pemetrexed for 30 min, pemetrexed was accumulated at 14- and 1.7-fold greater than that in control cells, respectively. Pemetrexed and methotrexate transport by hOAT3 was saturated at high concentrations with apparent Km values 28.2 microM and 76.6 microM, respectively. In addition, intrinsic activity (Vmax/Km) of pemetrexed and methotrexate transport by hOAT3 was 4.82 and 0.42 microl/min/mg protein, respectively, suggesting 11-fold higher transport of pemetrexed than methotrexate by hOAT3. Furthermore, loxoprofen, ibuprofen, pravastatin, and cefazolin, transport substrates of hOAT3, inhibited pemetrexed transport by hOAT3 with IC50 values, 34.2, 27.9, 76.3 and 650 microM, respectively. CONCLUSIONS: Pemetrexed is a superior substrate to methotrexate for hOAT3. Loxoprofen, ibuprofen, and cefazolin could cause drug-drug interactions when attaining high blood concentrations.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
PemetrexedSolute carrier family 22 member 6ProteinHumans
No
Substrate
Details