Pharmacokinetic characteristics of the novel anticancer agent CPT-11 and its active metabolite in plasma and lung lymph fluid following intravenous administration to sheep

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11, 100286-90-6) is one of the most promising novel anticancer agents, especia lly for lung cancer. 7-Ethyl-10-hydroxycamptothecin (SN-38), an active meta bolic of CPT-11, has much stronger cytotoxicity than CPT-11. The present st udy was designed to evaluate the distribution and behavior of CPT-11 and SN -38 in lung lymph circulation following intravenous infusion. Awake sheep w ith chronically instrumented lung lymph fistulas were prepared. The concent rations of CPT-11 and SN-38 in plasma and lung lymph fluid were measured af ter intravenous infusion of 100 mg/body of CPT-11 for 90 min. SN-38 constan tly showed higher lymph to plasma concentration ratios than those of CPT-11 , and the % area under the curve (AUC) ratio of SN-38/CPT-11 in lymph fluid was significantly higher than that in plasma. These data indicated that SN -38 distributed in lung tissue moved more easily into lung lymph fluid than CPT-11, and might be more rapidly metabolized in lung tissue than plasma. CPT-11 may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.