title: Paroxetine decreased plasma exposure of glyburide partly via inhibiting intestinal absorption in rats.
abstract: Accumulating evidences have shown that diabetes is often accompanied with depression, thus it is possible that oral antidiabetic agent glyburide and antidepressive agent paroxetine are co-administered in diabetic patients. The aim of this study was to assess interactions between glyburide and paroxetine in rats. Effect of paroxetine on pharmacokinetics of orally administered glyburide was investigated. Effect of naringin (NAR), an inhibitor of rat intestinal organic anion transporting polypeptides 1a5 (Oatp1a5), on pharmacokinetics of glyburide was also studied. The results showed that co-administration of paroxetine markedly reduced plasma exposure and prolonged Tmax of glyburide, accompanied by significant increase in fecal excretion of glyburide. Co-administration of naringin also significantly decreased plasma exposure of glyburide. Data from intestinal perfusion experiments showed that both paroxetine and naringin significantly inhibited intestinal absorption of glyburide. Caco-2 cells were used to investigate whether paroxetine and naringin affected intestinal transport of glyburide and fexofenadine (a substrate of Oatp1a5). The results showed that both paroxetine and naringin greatly inhibited absorption of glyburide and fexofenadine. All results gave a conclusion that co-administration of paroxetine decreased plasma exposure of glyburide in rats via inhibiting intestinal absorption of glyburide, which may partly be attributed to the inhibition of intestinal Oatp1a5 activity.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Weiman
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Kaijing
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China. Electronic address: liulee@yeah.net.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China. Electronic address: xdliu@cpu.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001692:Biological Transport; D018938:Caco-2 Cells; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005243:Feces / Q000737:chemistry; D044950:Flavanones / Q000494:pharmacology; D005905:Glyburide / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood* / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D044950:Flavanones; D007004:Hypoglycemic Agents; D029362:Organic Anion Transporters, Sodium-Independent; C421143:Slco1a5 protein, rat; D017374:Paroxetine; D016593:Terfenadine; C093230:fexofenadine; C005274:naringin; D005905:Glyburide
keywords: Caco-2 cells; Glyburide; Intestinal transport; Oral absorption; Organic anion transporting polypeptides; Paroxetine; Pharmacokinetics