Plasma pharmacokinetics and metabolism of the antitumour drug candidate 2′-benzoyloxycinnamaldehyde in rats

Abstract

The pharmacokinetics and metabolism of 2'-benzoyloxycinnamaldehyde (BCA) was characterized in male Sprague-Dawley rats as part of the preclinical evaluations for developing this compound as an antitumour agent. BCA was not detected in the plasma following either intravenous or oral dose, whereas its putative metabolites 2'-hydroxycinnamaldehyde (HCA) and o-coumaric acid were present at considerable levels. In separate pharmacokinetics studies, HCA exhibited a high systemic clearance and a large volume of distribution, whereas both pharmacokinetic parameters were much lower for o-coumaric acid. The terminal half-life of both metabolites was approximately 2 h. BCA was converted rapidly to HCA in rat serum, liver microsomes and cytosol in vitro; HCA was subsequently converted to o-coumaric acid in a quantitative manner only in the liver cytosol. In addition, the formation of o-coumaric acid was inhibited significantly by menadione, a specific inhibitor for aldehyde oxidase. Taken collectively, the results suggest that the rapid systemic clearance of HCA is likely due mainly to hepatic clearance occurring from aldehyde oxidase-catalysed biotransformation to o- coumaric acid. In conclusion, the present work demonstrates that the anticancer drug candidate BCA is highly likely to work as its active metabolite HCA in the body.

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

“…Cinnamaldehyde has been reported to induce ROS generation mainly in the mitochondria and inhibit growth of human cancer cells, but minimal cytotoxicity to normal cells 21,23,24 . However, the clinical applications of cinnamaldehyde have been limited by its poor bioavailability (a short half-life in blood) due to rapid oxidation of aldehyde group and lower drug efficacy than common anticancer drugs 21,25,26 .…”

Cinnamaldehydes in Cancer Chemotherapy

“…Lee et al . (, ) showed that BCA was not detected in the plasma following either intravenous or oral dosing in male Sprague–Dawley rats. Interestingly, HCA and o ‐coumaric acid, putative metabolites of BCA, were detected at considerable levels in the plasma of BCA‐treated rats.…”

“…Interestingly, HCA and o ‐coumaric acid, putative metabolites of BCA, were detected at considerable levels in the plasma of BCA‐treated rats. In separate pharmacokinetics studies, it was determined that the terminal half‐life of HCA and o ‐coumaric acid was approximately 2 h. Therefore, it is likely that HCA is an active metabolite of BCA, and the rapid systemic clearance of HCA in BCA‐treated rat could be due to hepatic clearance following a biotransformation reaction to o ‐coumaric acid, catalyzed by aldehyde oxidase (Lee et al , ).…”

Effects of a newly developed tricyclic PARP‐1 inhibitor, on ischemic stroke

“…The reaction was terminated at 0, 15, 45, and 80 min by the addition of 300 ml of ice-cold extraction solution (acetonitrile:formic acid 5 99.1:0.1 v/v; ES) containing carbamazepine (internal standard). The mixtures were then centrifuged at 3,000 rpm for 10 min and the supernatant was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/ MS) [Lee et al, 2009].…”

“…Blood samples ($350 ml each) were collected into heparin tubes, containing 10 ml heparin (50 IU/ml) at predetermined time points through the right jugular vein. Blood samples were centrifuged under refrigeration at 3,000 rpm for 10 min and kept frozen at À201C until analysis [Lee et al, 2009].…”