Pharmacokinetics and tissue distribution of betulinic acid in CD-1 mice

Betulinic acid is a naturally occurring pentacyclic triterpenoid. Betulinic acid has recently been selected by the National Cancer Institute for addit ion into the RAID (Rapid Access to Intervention Development) programme. The agent exhibits potential anti-tumour activity and functions in this regard via apoptosis, The objective of the present study was to determine the pha rmacokinetics of betulinic acid in CD-1 mice. Serum samples were obtained a t designed times after a single 250 or 500 mg/kg intraperitoneal (IP) dose of betulinic acid. Tissue samples (skin, heart, liver, spleen, kidney, lung , brain, colon, eaecum, ovary, uterus, thymus, lymph node, bladder, periren al fat, mammary gland and small intestine) were collected after betulinic a cid administration (500 mg/kg). Betulinic acid was extracted with methylene chloride and quantitatively analysed by HPLC/MS. Oleanolic acid and madeca ssic acid were used as internal standards. Pharmacokinetic parameters were calculated using the WinNonlin pharmacokinetic software package. A two-comp artment, first-order model was selected for pharmacokinetic modelling. The results showed that after UP 250 and 500 mg/kg betulinic acid, the serum co ncentrations reached peaks at 0.15 and 0.23 h, respectively. The 250 and 50 0 mg/kg above betulinic acid IP doses were found to have elimination half-l ives of 11.5 and 11.8 h and total clearances of 13.6 and 13.5 L/kg/h, respe ctively. The pharmacokinetic parameters observed for IP betulinic acid 500 mg/kg in the skin of mice were as follows: k(a) (h(-1)) 0.257, k(10) (h(-1) ) 0.234, t(1/2(alpha)) (h) 2.63, t(1/2(beta)) (h) 20.2, V (L/kg) 0.61, AUC (mu g/h/mL) 3504, T-max (h) 3.90 and C-max (mu g/mL) 300.9. The distributio n of betulinic acid in tissues at 24 h post-IP administration in a descendi ng order was as follows: perirenal fat, ovary, spleen, mammary gland, uteru s, bladder, lymph node, liver, small intestine, caecum, lung, thymus, colon , kidney, skin, heart and brain. Copyright (C) 1999 John Wiley & Sons, Ltd.