Carrier and dose effects on the pharmacokinetics of T-0128, a camptothecin analogue-carboxymethyl dextran conjugate, in non-tumor- and tumor-bearing rats.
T-0128 is a novel camptothecin (CPT) analogue (T-2513: 7-ethyl-10-aminopropyloxy-CPT)-carboxymethyl (CM) dextran conjugate via a Gly-Gly-Gly linker, with a molecular weight (MW) of 130 kDa. Our previous studies demonstrated that T-0128 has strong antitumor activity against human tumor xenografts that are highly refractory to CPT analogues attributable to the passive tumor targeting of released T-2513. This study examines the effects of carrier, dose, and tumor on T-0128 pharmacokinetics. To study carrier effect, tumor-bearing rats received one i.v. injection of fluorescein isothiocyanate (FITC)-labeled CM dextran with a different degree of substitution (DS) of the carboxymethylated groups and a different MW. Results showed that CM dextran from Dextran T-110 (MW 110 kDa) with a DS value of 0.4 is an appropriate drug carrier for T-0128 regarding plasma half-life and passive tumor targeting. To study dose and tumor effects, non-tumor- and tumor-bearing rats were treated with T-0128 doses ranging from 1 to 25 mg/kg (based on the amount of T-2513 bound to CM dextran). Dose-dependent pharmacokinetics of T-0128 were observed in both kinds of rats. The presence of tumor reduced the plasma half-life and systemic exposure of T-0128. The saturation of hepatic and splenic tissue uptake clearances (CLups), and a large contribution of the tumor CLup to the total body clearance explain these results. Overall, our data provide a rationale for the selection of the carrier for T-0128 and a need for pharmacokinetic studies to evaluate the influences of tumor on the drug disposition.
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Kashima 3-16-89, Yodogawa-ku, 532-8505, Osaka, Japan. m-harada@tanabe.co.jp
M
M
Harada
J
J
Murata
Y
Y
Sakamura
H
H
Sakakibara
S
S
Okuno
T
T
Suzuki
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives*; D002240:Carbohydrate Sequence; D002460:Cell Line; D002845:Chromatography; D003911:Dextrans / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D019772:Topotecan / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D000972:Antineoplastic Agents, Phytogenic; D003911:Dextrans; D011355:Prodrugs; D019772:Topotecan; C014392:carboxymethyl dextran; C410031:T 0128; D002166:Camptothecin