title: Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats.
abstract: OBJECTIVE
  Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin.
  
  
  METHODS
  The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry.
  
  
  RESULTS
  The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation.
  
  
  CONCLUSIONS
  Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.|Graduate School of Chulalongkorn University, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Kunan
authors.initials: K
authors.lastname: Bangphumi
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.|Graduate School of Chulalongkorn University, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Chuleeporn
authors.initials: C
authors.lastname: Kittiviriyakul
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.|Chulalongkorn University Drugs and Health Product Innovation Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Pasarapa
authors.initials: P
authors.lastname: Towiwat
authors.affiliation: Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.|Chulalongkorn University Drugs and Health Product Innovation Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Pornchai
authors.initials: P
authors.lastname: Rojsitthisak
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. Phisit.K@chula.ac.th.|Chulalongkorn University Drugs and Health Product Innovation Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. Phisit.K@chula.ac.th.
authors.forename: Phisit
authors.identifier: http://orcid.org/0000-0001-7994-4503
authors.initials: P
authors.lastname: Khemawoot
mesh_terms: D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D003474:Curcumin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000097:blood / Q000378:metabolism / Q000652:urine; D006207:Half-Life; D065669:Hepatobiliary Elimination; D006868:Hydrolysis; D007275:Injections, Intravenous; D066237:Intestinal Elimination; D008297:Male; D008657:Metabolic Clearance Rate; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D012995:Solubility; D013386:Succinates / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry
chemical_list: D018712:Analgesics, Non-Narcotic; D020719:Glucuronides; D011355:Prodrugs; D013386:Succinates; C000614237:curcumin diethyl disuccinate; D003474:Curcumin