Decreased urinary secretion of belotecan in folic acid-induced acute renal failure rats due to down-regulation of Oat1 and Bcrp.
The effects of folic acid-induced acute renal failure on the renal excretion of belotecan were investigated in rats after intravenous administration. Both glomeruli and renal tubules were seriously damaged by folic acid-induced acute renal failure. The renal excretion clearance, CLr, of belotecan was significantly decreased by folic acid-induced acute renal failure. Furthermore, glomerular filtration rate and secretion clearance of the drug were dramatically decreased by folic acid-induced acute renal failure. In vivo renal uptake of belotecan was inhibited by p-aminohippurate, whereas renal excretion was inhibited by GF120918, but not by verapamil and bromosulphalein. This indicates that Oat1/3 and Bcrp are involved in the renal uptake and urinary excretion of belotecan, respectively. Both mRNA and protein levels of Oat1, Oat3 and Bcrp were significantly decreased in folic acid-induced acute renal failure rats. Based on the finding that belotecan is a substrate of OAT1 but not of OAT3, the decrease in CLr of belotecan in folic acid-induced acute renal failure could, therefore, mainly be attributed to the down-regulation of Oat1 and Bcrp, in addition to the decrease in glomerular filtration rate.
Jin
Q-R
QR
College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Shim
W-S
WS
Choi
M-K
MK
Tian
G-Y
GY
Song
I-S
IS
Yang
S-G
SG
Kim
D-D
DD
Chung
S-J
SJ
Shim
C-K
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005492:Folic Acid / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007202:Indicators and Reagents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D014803:Vitamin B Complex / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000166:Acridines; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D007202:Indicators and Reagents; D027362:Organic Anion Transport Protein 1; C421043:Slc22a6 protein, rat; D044005:Tetrahydroisoquinolines; D014803:Vitamin B Complex; C116963:belotecan; D005492:Folic Acid; D014700:Verapamil; C083501:Elacridar; D002166:Camptothecin; D010130:p-Aminohippuric Acid