Effects of Experimental Hyperlipidemia on the Pharmacokinetics of Tadalafil in Rats

Joo Hyun Lee1, Ju-Hee Oh1, Young-Joo Lee2

1Division of Biopharmaceutics, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Korea.
2Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 130-701, Korea.


Purpose. 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.

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J Pharm Pharm Sci, 15 (4): 528-537, 2012

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