PT  - JOURNAL ARTICLE
AU  - Kaneda, Norimasa
AU  - Nagata, Hiroshi
AU  - Furuta, Tomio
AU  - Yokokura, Teruo
TI  - Metabolism and Pharmacokinetics of the Camptothecin Analogue CPT-11 in the Mouse
DP  - 1990 Mar 15
TA  - Cancer Research
PG  - 1715--1720
VI  - 50
IP  - 6
4099  - http://cancerres.aacrjournals.org/content/50/6/1715.short
4100  - http://cancerres.aacrjournals.org/content/50/6/1715.full
SO  - Cancer Res1990 Mar 15; 50
AB  - A new water-soluble derivative of camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), did not exhibit potent antitumor activity in vitro against experimental tumor cells. The 50% effective doses of CPT-11 against KB and L1210 cells were 1100 and 5500 ng/ml, respectively. These values were markedly higher than those of camptothecin (CPT, 0.98 and 3.7 ng/ml) or 7-ethyl-10-hydroxycamptothecin (SN-38, 0.37 and 3.6 ng/ml). CPT-11 was found to be converted into SN-38 in mouse serum. In vitro incubation of CPT-11 in mouse serum or tissue homogenate enhanced the growth-inhibitory activity much more than that expected from the concentration of CPT-11. This enhancement of the activity coincided with that expected from the SN-38 concentration in incubated serum or homogenate, though the contribution of CPT-11 could not be refuted. SN-38 is considered to play a major role in the antitumor activity when CPT-11 is incubated in serum or homogenate. The plasma CPT-11 concentration decreased biexponentially after i.v. administration of CPT-11 into mice with a biological half-life of 0.8 to 1.1 h. The area under the plasma CPT-11 concentration-time curve showed dose dependency. The SN-38 concentration decreased for the first 30 min after administration and was then maintained for a few hours at about 0.1 µg/ml after i.v. administration of 20 and 40 mg/kg of CPT-11 followed by the log-linear terminal phase with a half-life of about 2 h which was independent of the dose. It is suggested that the maintenance of plasma SN-38 concentration might be necessary for it to exhibit antitumor activity in vivo. ©1990 American Association for Cancer Research.