Abstract 2666: Pharmacokinetic and biodistribution in mice of sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, a curcumin derivative
Authors: Valduga Claudete J. , Leonardo Gilvan P. , Maria Durvanei A. , Santos Reginaldo P. , Santos Rene M. , Santos Maria A. , Quincoces Jose A. 
Published: February 2011

Introduction and Objective: 1,5-diarylpenta-1,4-dien-3-one and derivatives as 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-1,4-dien-3-one (1) are phenolic compounds with structure similar to curcumin, a natural substance with a large variety of biological effects. UNIBAN's Organic Synthesis Group has been working for some years with compound 1, which shows a good antitumor activity and a low toxicity as confirmed by the in vivo studies. Compound 1 was converted in its respective monosodium salt (2) in order to become water-soluble and to facilitate in vivo studies. Here we evaluated the pharmacokinetic profile of the water-soluble sodium salt, 2, and identified the main metabolites found in plasma and tissues of health mice.

Materials and Methods: Nine groups of four healthy mice were injected with a single dose of compound 1 (50mg/Kg) into the retro-orbital venous plexus. Blood samples were collected from 5 min. to 24h, centrifuged and mice were sacrificed. One group was taken as control. Compound 2 or 1 and/or its metabolites were extracted from plasma and organs (heart, liver, spleen, brain, lymph node, kidney and lung and intestine) with methanol and methanol/chloroform 1:2, respectively. Solvents were concentrated under nitrogen flow, reconstituted and analyzed in HPLC and LC-MS. The pharmacokinetic parameters of compound 1 were calculated using a multicompartimental model by means of a computer software.

Results: When plasma samples were analyzed we only found compound 1 and metabolites. Regarding pharmacokinetic, the sodium salt or its neutral form disappeared from plasma after thirteen minutes of injection, the half-life is very short although its neutral form show a half-life around of 6 hours, according to literature. T1/2β of compound 1 was 14.1±2.7 minutes, AUC 2425.9±113.6 μg.min/mL, CL 18.0±0.4 mL/min, Vdss 367.1±77.5 mL/kg. Due to the fact of 2 be water-soluble it is quickly metabolized mainly by cytochrome P450 enzymes. We identified mono- and bis-O-demethylated, double bond-reduced, both double bond- and carbonyl-reduced, bis-hydroxylated, sulphated and glucuronidated metabolites being excreted by gastrointestinal tract. Some of these metabolites were found in other analyzed tissues too.

Conclusion: The conversion of compound 1 in its respective water-soluble sodium salt, 2, has the great advantage of avoiding toxic organic solvents, but its half-life is drastically reduced compared to neutral form (1), due to its quick metabolization, producing molecules that suffer only phase I or phase II metabolism and as a last resort both phase I and II happened simultaneously on the same molecule. Probably due to the quick metabolization of the ionic form, the conversion of 1 in its respective sodium salt gave rise to a slight reduction on antitumoral activity when compared to its neutral form, as saw in previous studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2666.