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Pharmacokinetics and tissue distribution of betulinic acid in CD-1 mice
G O Udeani1, G M Zhao, Y Geun Shin
1Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. gudeani@uic.edu
Abstract:
Betulinic acid is a naturally occurring pentacyclic triterpenoid. Betulinic acid has recently been selected by the National Cancer Institute for addition into the RAID (Rapid Access to Intervention in 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 pharmacokinetics of betulinic acid in CD-1 mice. Serum samples were obtained at 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, caecum, ovary, uterus, thymus, lymph node, bladder, perirenal fat, mammary gland and small intestine) were collected after betulinic acid administration (500 mg/kg). Betulinic acid was extracted with methylene chloride and quantitatively analysed by HPLC/MS. Oleanolic acid and madecassic acid were used as internal standards. Pharmacokinetic parameters were calculated using the WinNonlin pharmacokinetic software package. A two-compartment, first-order model was selected for pharmacokinetic modelling. The results showed that after IP 250 and 500 mg/kg betulinic acid, the serum concentrations reached peaks at 0.15 and 0.23 h, respectively. The 250 and 500 mg/kg above betulinic acid IP doses were found to have elimination half-lives of 11.5 and 11.8 h and total clearances of 13.6 and 13.5 L/kg/h, respectively. 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 (microg/h/mL) 3504, T(max) (h) 3.90 and C(max) (microg/mL) 300.9. The distribution of betulinic acid in tissues at 24 h post-IP administration in a descending order was as follows: perirenal fat, ovary, spleen, mammary gland, uterus, bladder, lymph node, liver, small intestine, caecum, lung, thymus, colon, kidney, skin, heart and brain.
Insights
This study investigated the pharmacokinetics of betulinic acid in mice, revealing its distribution and elimination patterns after intraperitoneal administration. The findings provide crucial data for understanding betulinic acid
Area of Science:
- Pharmacology and Toxicology
- Natural Products Chemistry
- Cancer Research
Background:
- Betulinic acid, a pentacyclic triterpenoid, exhibits potential anti-tumor activity through apoptosis.
- It has been selected by the National Cancer Institute for the RAID program.
- Understanding its pharmacokinetic profile is essential for therapeutic development.
Purpose of the Study:
- To determine the pharmacokinetics of betulinic acid in CD-1 mice.
- To analyze serum and tissue distribution after intraperitoneal administration.
- To establish key pharmacokinetic parameters for betulinic acid.
Main Methods:
- Mice received single intraperitoneal doses of 250 or 500 mg/kg betulinic acid.
- Serum samples were collected at timed intervals.
- Tissue samples were analyzed using HPLC/MS after methylene chloride extraction.
- Pharmacokinetic parameters were calculated using a two-compartment, first-order model via WinNonlin software.
Main Results:
- Serum concentrations peaked rapidly (0.15-0.23 h) with elimination half-lives of approximately 11.5-11.8 h.
- Total clearance was consistent at ~13.5 L/kg/h.
- Betulinic acid distributed widely in tissues, with highest concentrations in perirenal fat, ovary, and spleen at 24 hours post-administration.
Conclusions:
- Betulinic acid demonstrates a predictable pharmacokinetic profile in mice following intraperitoneal administration.
- The drug distributes to various tissues, with significant accumulation in adipose tissue and reproductive organs.
- These pharmacokinetic data are vital for further preclinical and clinical development of betulinic acid as an anti-cancer agent.