DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 475

transport activity than the wild type. 110 These results indicate that the binding sites of
OCTN2 for carnitine and organic cations significantly overlap but are not identical.
Based on the search for OAT isoforms, we identified a clone with relatively ubiq-
uitous tissue distribution and named it carnitine transporter 1 (CT1). 111 CT1 medi-

ated the high-affinity transport of L-carnitine ( K m = 25 μ M) in a partially sodium-

dependent manner. Octanoylcarnitine, acetylcarnitine, and -butyrobetaine potently

inhibited the CT1-mediated carnitine transport.

MDR1/P-Glycoprotein ABCB MDR1 is a member of the ABC transporter super-
family. MDR1 actively extruded from the cells drugs with diverse structures, such
as Vinca alkaloids, steroids, cyclosporines, tacrolimus, anthracyclines, and miscella-
neous hydrophobiccations. 66 Although the cellular drug efflux mediated by Pgp was
first identified in cancer cells, Pgp was found to be highly expressed in a number of nor-
mal tissues, such as liver, pancreas, kidney, colon, and jejunum. In the kidney, MDR1
was found to be concentrated particularly on the apical surface of epithelial cells of
the proximal tubules, where it secretes various drug substrates into the lumen. 112 The
finding that a cardiac glycoside digoxin is actively secreted via Pgp in renal proximal
tubules is clinically important for transporter-mediated drug interactions.

MATE1 Very recently, Otsuka et al. show that MATE1, a human and mouse or-
tholog of the multidrug and toxin extrusion family conferring multidrug resistance
on bacteria, is expressed primarily in the kidney and liver, where it is localized to
the luminal membranes of the renal tubules and bile canaliculi. 113 When expressed
in HEK293 cells, MATE1 mediates H + -coupled electroneutral exchange of TEA and
MPP + . Its substrate specificity is similar to those of renal and hepatic H + -coupled
organic cations export. Thus, MATE1 appears to be the long-searched-for polyspe-
cific organic cation exporter that directly transports toxic organic cations into urine
and bile.

15.3. REGULATION OF RENAL DRUG TRANSPORTERS

15.3.1. Gender and Developmental Differences

Gender differences in mRNA and/or protein expression have been reported for
OAT1, 114 , 115 OAT2, 34 , 115-117 OAT3, 114-116 URAT1, 118 and OCT2, 119 , 120 thereby sug-
gesting that some OAT members and OCT2 are regulated by sex hormones. The mouse
Oat1 mRNA levels were higher in the male kidney than in the female kidney. Rat Oat2
mRNA expression was higher in the female kidney than in the male kidney or liver.
In contrast, the mouse Oat2 mRNA levels were highest in both kidneys and low in
the male liver. In the male liver, rat Oat3 mRNA expression was detected. The mouse
Urat1 mRNA levels were higher in the male kidney than in the female kidney. The
rat Oct2 mRNA levels were higher in the male kidney than in the female kidney. De-
velopmental changes of expression have been reported in OATs 115 , 121 , 122 ; the mRNA
expression levels of OAT1, OAT2, and OAT3 increased during postnatal development.