EFFECT OF THE NONIMMUNOSUPPRESSIVE CYCLOSPORINE ANALOG SDZ PSC-833 ONCOLCHICINE AND DOXORUBICIN BILIARY-SECRETION BY THE RAT IN-VIVO

Colchicine and doxorubicin are secreted into bile as a major pathway o f their elimination. Colchicine and doxorubicin are also substrates fo r P-glycoprotein, and P-glycoprotein has been demonstrated to be prese nt at the liver canalicular membrane. Cyclosporin (CsA) inhibits colch icine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the bilia ry secretion of colchicine and doxorubicin were investigated. SDZ PSC- 833 given at a bolus dose of 2 mg/kg promptly decreased colchicine bil iary clearance from 9.05+/-0.2 to 2.41+/-0.43 ml min(-1) kg(-1) (P<0.0 01) and the colchicine bile/plasma ratio from 146+/-8 to 35+/-5 (P<0.0 01). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5+/-3 vs post-SDZ PSC-833: 2.48+/-0.94 m1 min(-1) kg(-1); P = 0.06) and the doxorubicin bile/plasma ratio (basal: 228+/-64 vs post-SDZ PS C-833: 48+/-22; P<0.01). Colchicine renal secretion was completely inh ibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive tra nsport of the multidrug-resistance substrates colchicine and doxorubic in and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired eliminati on of cytotoxic agents will need to be considered if SDZ PSC-833 is us ed to chemosensitize cancer cells.