Differential involvement of multidrug resistance-associated protein 1 and P-glycoprotein in tissue distribution and excretion of grepafloxacin in mice.
The involvement of multidrug resistance-associated protein 1 (Mrp1) and P-glycoprotein (mdr1) in the tissue distribution and excretion of grepafloxacin (GPFX), a fluoroquinolone antibiotic, was investigated using gene-deficient mice [mdr1a(-/-), mdr1a/1b(-/-), and mrp1(-/-)]. The plasma concentration-time profile of GPFX in mrp1(-/-) was nearly identical to that in mrp1(+/+), whereas that in mdr1a/1b(-/-) was higher than that in mdr1a/1b(+/+). The urinary clearance of GPFX in mdr1a/1b(-/-) was lower than that in mdr1a/1b(+/+), suggesting that the urinary excretion of GPFX is at least partially mediated by mdr1. The tissue-to-plasma concentration ratios during the beta-phase (K(p beta),) was significantly higher in the heart, trachea, kidney, spleen, and brown fat of mrp1(-/-) than those in mrp1(+/+). In MRP1-transfected LLC-PK1 cells, the efflux of GPFX after preloading into the cells was higher than that observed in the parent cell lines. These results suggest that GPFX is a substrate of MRP1 and that its distribution to these tissues might be limited by Mrp1. On the other hand, a higher K(p beta), and of GPFX in mdr1a(-/-) mdr1a/1b(-/-) compared with mdr1a/1b(+/+) was observed only in the brain. GPFX was efficiently distributed to the lung parenchyma cells and pulmonary airspaces, including the epithelial lining fluid and macrophages that are the pharmacological target of GPFX, although the contribution of Mdr1 and Mrp1 to such distribution seems to be minor. Thus, the present findings reveal that the disposition of GPFX is at least in part governed by these two ABC transporters and that both Mrp1 and Mdr1 are involved in the limited distribution of GPFX to the distinct tissues, including pharmacological and/or toxicological targets by an active efflux mechanism.
Sasabe
Hiroyuki
H
Department of Drug Metabolism, Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan.
Kato
Yukio
Y
Suzuki
Takashi
T
Itose
Minoru
M
Miyamoto
Gohachiro
G
Sugiyama
Yuichi
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D024841:Fluoroquinolones / Q000097:blood* / Q000494:pharmacology / Q000652:urine*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000097:blood* / Q000494:pharmacology / Q000652:urine*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D024841:Fluoroquinolones; D010879:Piperazines; C075375:grepafloxacin