Tissue distribution of 10-methoxycamptothecin and its metabolite 10-hydroxycamptothecin in rats by a RP-HPLC method with fluorescence detection/UV detection

Abstract

Both 10-methoxycamptothecin (MCPT) and 10-hydroxycamptothecin (HCPT) are the natural derivatives of camptothecin (CPT) isolated from Camptotheca acuminata, possessing broad-spectrum antitumor activity. HCPT was identified as a major metabolite of MCPT in rats. In the present study, liquid chromatography coupled with a fluorescence detector (or a UV detector) was used for the study of tissue distribution of MCPT and its metabolite HCPT in rats after i.v. administration (5mg/kg). The results indicated that MCPT was rapidly absorbed and readily diffused into all sampling tissues (heart, liver, spleen, lung, kidney, brain) after i.v. administration.MCPT was accumulated to a very high level in lung tissues which could be quantified until 120 h, and the concentration was up to 1000 times higher than that in plasma sample. The AUC 0-∞ of MCPT in lung tissues was 3888.45 ± 203.59µg•h/mL which is about 650 and 40000 times as that in liver and brain tissues. The level of MCPT reached the maximum right after i.v. administration then declined in liver, spleen, kidney, heart, brain tissues and was detectable until 72h in liver and heart tissues, 48h in spleen and kidney tissues, and 24h in brain tissues. HCPT showed similar concentration-time profiles to MCPT, where HCPT concentration were relatively steady from 12h to 48 h and could be quantified in lung tissues until 120h, in liver, spleen, kidney, heart and brain tissues until 72h. The maximum concentration of HCPT was very low whereas it kept steady from 2h until 48h, giving an AUC 0-∞ much higher than that of MCPT in brain, and also higher than the AUC 0-∞ of HCPT in heart and spleen tissues.

Synthesis, antitumor activity and pharmacokinetic study of 10‐propionyloxy camptothecin in rats

“…A formulation of PCPT (2.5 mg/mL) was prepared by mixing PCPT with DMSO-PEG-400-0.01 mol/L H 3 PO 4 (5:45:50, v/v/v) (Shao et al, 2015;Zhong, Li, Xu, Du, & Zhang, 2003). Animal handling procedures were according to standard operating procedures approved by the Institutional Animal Care and Use Committee at Northeast Forestry University.…”

“…The binary gradient mobile phases were water (containing 5% ACN) as mobile phase A and ACN as mobile phase B. The time program of the gradient was the same as for our previous studies (Liu et al, 2014;Shao et al, 2015;. The total data acquisition time was 25 min.…”

“…Animal handling procedures were according to standard operating procedures approved by the Institutional Animal Care and Use Committee at Northeast Forestry University. A formulation of PCPT (2.5 mg/mL) was prepared by mixing PCPT with DMSO-PEG-400-0.01 mol/L H 3 PO 4 (5:45:50, v/v/v) (Shao et al, 2015;Zhong, Li, Xu, Du, & Zhang, 2003).…”