Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo.
Colchicine and doxorubicin are secreted into bile as a major pathway of their elimination. Colchicine and doxorubicin are also substrates for P-glycoprotein, and P-glycoprotein has been demonstrated to be present at the liver canalicular membrane. Cyclosporin (CsA) inhibits colchicine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the biliary secretion of colchicine and doxorubicin were investigated. SDZ PSC-833 given at a bolus dose of 2 mg/kg promptly decreased colchicine biliary clearance from 9.05 +/- 0.2 to 2.41 +/- 0.43 ml min-1 kg-1 (P < 0.001) and the colchicine bile/plasma ratio from 146 +/- 8 to 35 +/- 5 (P < 0.001). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5 +/- 3 vs post-SDZ PSC-833: 2.48 +/- 0.94 ml min-1 kg-1; P = 0.06) and the doxorubicin bile/plasma ratio (basal: 228 +/- 64 vs post-SDZ PSC-833: 48 +/- 22; P < 0.01). Colchicine renal secretion was completely inhibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive transport of the multi-drug-resistance substrates colchicine and doxorubicin and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired elimination of cytotoxic agents will need to be considered if SDZ PSC-833 is used to chemosensitize cancer cells.
Speeg
K V
KV
Department of Medicine, University of Texas Health Science Center, San Antonio 78284.
Maldonado
A L
AL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000032:analysis / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000032:analysis / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004351:Drug Resistance; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D004317:Doxorubicin; C070272:valspodar; D003078:Colchicine