title: Effects of experimental hyperlipidemia on the pharmacokinetics of tadalafil in rats.
abstract: OBJECTIVE
  Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia.
  
  
  METHODS
  Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding.
  
  
  RESULTS
  Hyperlipidemia dramatically increased tadalafil's the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil.
  
  
  CONCLUSIONS
  The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 130-701, Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Oh
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002243:Carbolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D058986:Phosphodiesterase 5 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D020442:Poloxamer / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068581:Tadalafil
chemical_list: D001798:Blood Proteins; D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D020442:Poloxamer; D000068581:Tadalafil