title: Alteration of the intravenous and oral pharmacokinetics of valsartan via the concurrent use of gemfibrozil in rats.
abstract: The present study aimed to examine the potential pharmacokinetic drug interaction between valsartan and gemfibrozil. Compared with the control given valsartan (10 mg/kg) alone, the concurrent use of gemfibrozil (10 mg/kg) significantly (p < 0.05) increased the oral exposure of valsartan in rats. In the presence of gemfibrozil, the Cmax and AUC of oral valsartan increased by 1.7- and 2.5-fold, respectively. Consequently, the oral bioavailability of valsartan was significantly higher (p < 0.05) in the presence of gemfibrozil compared with that of the control group. Furthermore, the intravenous pharmacokinetics of valsartan (1 mg/kg) was also altered by pretreatment with oral gemfibrozil (10 mg/kg). The plasma clearance of valsartan was decreased by two-fold in the presence of gemfibrozil, while the plasma half-life was not altered. In contrast, both the oral and intravenous pharmacokinetics of gemfibrozil were not affected by the concurrent use of valsartan. The cellular uptake of valsartan and gemfibrozil was also investigated by using cells overexpressing OATP1B1 or OATP1B3. Gemfibrozil and gemfibrozil 1-O-β glucuronide inhibited the cellular uptake of valsartan with IC50 values (µm) of 39.3 and 20.4, respectively, in MDCK/OATP1B1, while they were less interactive with OATP1B3. The cellular uptake of gemfibrozil was not affected by co-incubation with valsartan in both cells. Taken together, the present study suggests the potential drug interaction between valsartan and gemfibrozil, at least in part, via the OATP1B1-mediated transport pathways during hepatic uptake. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: BK21 Plus Project Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 410-820, Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: BK21 Plus Project Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 410-820, Korea.
authors.forename: Bong Jin
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: BK21 Plus Project Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 410-820, Korea.
authors.forename: Lingxuan
authors.initials: L
authors.lastname: Mo
authors.affiliation: BK21 Plus Project Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 410-820, Korea.
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D004285:Dogs; D004347:Drug Interactions; D015248:Gemfibrozil / Q000097:blood / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D000068756:Valsartan / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D000960:Hypolipidemic Agents; D029362:Organic Anion Transporters, Sodium-Independent; D000068756:Valsartan; D015248:Gemfibrozil
keywords: OATP1B1; OATP1B3; drug interaction1; gemfibrozil; tvalsartan