Co-administration of paroxetine increased the systemic exposure of pravastatin in diabetic rats due to the decrease in liver distribution.
1. Liver distribution and systemic exposure of pravastatin were the determinant factors of efficacy and toxicity of pravastatin. Aim of the present study was to investigate the effect of paroxetine on the liver distribution and systemic exposure of pravastatin in diabetic rats induced by combining high fat diet (HFD) and low-dose streptozotocin (STZ). 2. Plasma concentrations and liver distribution of pravastatin were measured in the presence of paroxetine. Effect of paroxetine on pravastatin excretion via bile, intestine, feces and urine, as well as pravastatin absorption via intestine was documented. Freshly isolated hepatocytes and Caco-2 cells were used to investigate the effect of paroxetine on pravastatin transport. 3. Paroxetine increased the systemic exposure of pravastatin and decreased hepatic distribution of pravastatin in diabetic rats. In vitro, paroxetine inhibited the hepatic uptake of pravastatin and promoted the efflux of pravastatin in freshly isolated hepatocytes, which may partly explain the decreased hepatic distribution of pravastatin by paroxetine. It was also observed that paroxetine promoted the absorption of pravastatin via jejunum and the uptake of pravastatin in Caco-2 cells. 4. We concluded that paroxetine increased the systemic exposure of pravastatin partly via promoting absorption via jejunum and inhibiting hepatic uptake of pravastatin.
a Key Laboratory of Drug Metabolism and Pharmacokinetics , China Pharmaceutical University , Nanjing , China and.
Feng
F
Li
Dan
D
Xu
Nan
N
Shu
Zeyu
Z
Zhong
Mian
M
Zhang
Can
C
Liu
Zhaoli
Z
Ling
Li
L
Liu
Xiaodong
X
Liu
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001826:Body Fluids / Q000737:chemistry; D002219:Carbamates / Q000494:pharmacology; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017374:Paroxetine / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D017035:Pravastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects
D002219:Carbamates; D010880:Piperidines; D017374:Paroxetine; C072379:repaglinide; D017035:Pravastatin
Diabetes; drug interactions; freshly isolated hepatocytes; intestinal absorption; liver distribution; paroxetine; pharamcokinetics; pravastatin