Effect of cyclosporine on colchicine secretion by the kidney multidrug transporter studied in vivo.
The multidrug resistance (MDR) transport protein is a normal constituent of proximal renal tubules although its function has not been defined in vivo. We find that colchicine, an MDR substrate, is secreted into urine by a process which is distinct from the organic cation transporter responsible for tetraethylammonium and N-methylnicotinamide secretion. Cyclosporine (CsA), which reverses MDR in vitro presumably by inhibiting the MDR transporter, inhibits colchicine renal secretion but does not inhibit the net secretion of the organic cation, ranitidine, or the organic anion, p-aminohippurate. After CsA (2 mg/kg i.v.), colchicine renal clearance decreased from 6.23 +/- 0.46 to 3.58 +/- 0.31 ml/min.kg (P less than .05), glomerular filtration rate was unchanged (4.21 +/- 0.08 and 3.88 +/- 0.17 ml/min.kg, before and after CsA, respectively; P = .09) and colchicine secretory ratio decreased from 1.48 +/- 0.11 to 0.92 +/- 0.07 (P less than .05). Cremophor (CsA vehicle) increased colchicine renal clearance (6.77 +/- 0.29 to 7.7 +/- 0.3 ml/min.kg, P less than .05) and colchicine secretory ratio (1.425 +/- 0.071 to 1.621 +/- 0.061, P less than .05). The inhibition of colchicine secretion was long-lived lasting at least 30 hr after CsA. Thus, colchicine is actively secreted into urine by the multidrug transporter in vivo. CsA profoundly inhibits colchicine secretion into urine while having no effect on the secretion of the organic cation ranitidine or the organic anion p-aminohippurate.
Speeg
K V
KV
Department of Medicine, University of Texas Health Science Center, San Antonio.
Maldonado
A L
AL
Liaci
J
J
Muirhead
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D003078:Colchicine / Q000378:metabolism*; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011899:Ranitidine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D010130:p-Aminohippuric Acid / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D016572:Cyclosporine; D011899:Ranitidine; D003078:Colchicine; D010130:p-Aminohippuric Acid