DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 477

without affecting its surface expression. 136 As a result, glycosylation could also be

responsible for substrate recognition.

15.4. RENAL HANDLING OF SELECTED DRUGS

15.4.1. Cephalosporin Antibiotics

Cephalosporin antibiotics are suggested not only to be filtered through the glomeruli
but also secreted actively by the proximal tubules. Cephalosporins inhibited PAH
uptake in rat renal slices 137 and renal plasma membrane vesicles. 138 Cephaloridine,
a cephalosporin that possesses both anionic and cationic moieties inhibited PAH
transport but not NMN transport in basolateral membrane vesicles. 139 Cephalosporin
antibiotics are thus considered to be secreted by the proximal tubule via the PAH
transport system. 8 Consistent with these results, we have observed that rOat1 as well
as rOat3 interacts with various cephalosporin antibiotics. 140 , 141
Using proximal tubular cells stably expressing human OAT1, OAT3, and OAT4
(S 2 -hOAT1, S 2 -hOAT3, S 2 -OAT4), we elucidated the interaction of human OATs
with various cephalosporin antibiotics. 142 All of cephalosporin antibiotics used
(cephalothin, cefoperazone, cefazolin, ceftriaxone, cephaloridine, cefotaxime, ce-
fadroxil, and cefamandole) significantly inhibited organic anion uptake mediated by
hOAT1, hOAT3, and OAT4 in a competitive manner.

15.4.2. Diuretics

Diuretics cause natriuresis and are therefore used to treat patients with volume over-
load, including hypertension, liver cirrhosis, nephrotic syndrome, and congestive heart
failure. 143 Thiazides and loop diuretics exhibit their diuretic effects from the luminal
side by inhibiting the Na + -Cl - cotransporter of the distal tubule and the Na + -K + -2Cl -
cotransporter of the loop of Henle, respectively. 143 In addition, because the binding
of diuretics to plasma proteins is generally high (more than 90%), tubular secretion is
the main route of urinary excretion of the diuretics. Tubular secretion has thus been
thought to play a critical role in the action of loop and thiazide diuretics. Renal tubular
secretion of diuretics has been demonstrated in studies dealing with the secretion of
bumetanide and furosemide in the isolated perfused rat kidney 144 , 145 and renal tubular
secretion of chlorothiazide and hydrochlorothiazide in the avian kidney. 146 Thiazide
and loop diuretics, which both contain a sulfamoyl group (sulfonamide diuretics)
as a common chemical characteristic, are weak organic acids. Consistent with this,
the involvement of the organic anion transport system in the tubular secretion of
diuretics has been suggested in studies including bumetanide inhibition of the PAH
transport in rat renal slices 147

and the PAH inhibition of furosemide excretion in the

rabbit. 148
Using S 2 -hOATs, we elucidated the interaction of human OATs with various
diuretics. 149 Diuretics tested (i.e., thiazides, loop diuretics, and carbonic anhydrase
inhibitors) inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and