title: Differential effects of pravastatin on the pharmacokinetics of paroxetine in normal and diabetic rats.
abstract: 1. Diabetes is often accompanied with depression and hypercholesterolemia. It is possible that paroxetine and pravastatin are co-administered to diabetic patients. The aim of this study was to research the differential effect of pravastatin on plasma exposure of paroxetine in normal and diabetic rats. 2. Pharmacokinetics of paroxetine was investigated following oral administration of paroxetine with and without pravastatin in normal and diabetic rats. Effects of pravastatin on metabolism, intestinal absorption and hepatic uptake of paroxetine were investigated. Activity and expression of hepatic Oatp1 and Oatp2 were also assessed. 3. Pravastatin decreased plasma exposure of paroxetine in normal rats, but increased exposure of paroxetine in diabetic rats. Pravastatin neither affected metabolism nor intestinal absorption of paroxetine. Data from hepatocytes demonstrated that hepatic uptake of paroxetine were involved in Oatp1 and Oatp2. Diabetes suppressed Oatp1 activity and expression, but enhanced Oatp2 activity and expression. Pravastatin stimulated Oatp1 but inhibited Oatp2 activity. 4. We concluded that differential effects of pravastatin on plasma exposure of paroxetine in normal and diabetic rats was partly due to the fact that diabetes suppressed Oatp1 activity and expression but enhanced Oatp2 activity and expression as well as that pravastatin stimulated Oatp1 activity but inhibited Oatp2 activity.
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Zhao-Li
authors.initials: ZL
authors.lastname: Ling
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Ze-Yu
authors.initials: ZY
authors.lastname: Zhong
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001692:Biological Transport; D003921:Diabetes Mellitus, Experimental; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D017374:Paroxetine / Q000378:metabolism*; D017035:Pravastatin / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*
chemical_list: D000924:Anticholesteremic Agents; D017374:Paroxetine; D017035:Pravastatin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Freshly isolated hepatocytes; organic anion-transporting polypeptides; paroxetine; pharmacokinetics; pravastatin