title: Effects of serum lipoproteins on cyclosporine A cellular uptake and renal toxicity in vitro.
abstract: In-vitro studies were performed to shed light on previous findings that showed increased uptake of cyclosporine A in the kidneys and liver of hyperlipidemic rats, and increased signs of kidney toxicity. Hepatocytes were obtained from rats, cultured, and exposed to a diluted serum from hyperlipidemic rats. Some cells were also exposed to lipid-lowering drugs. After washing out the rat serum or lipid-lowering drugs, cells were exposed to cyclosporine A embedded in serum lipoproteins. Pretreatment with hyperlipidemic serum and lipid-lowering drugs was associated with an increased uptake of cyclosporine A. As expected, atorvastatin caused an increase in low density lipoprotein receptor and a decrease in MDR1A mRNA in the hepatocytes. A decrease in NRK-52E rat renal tubular cellular viability caused by cyclosporine A was noted when cells were preincubated with diluted hyperlipidemic serum. This was matched with evidence of hyperlipidemic-serum-associated increases in the NRK-52E cellular uptake of cyclosporine A and rhodamine-123. The findings of these experiments suggested that in hyperlipidemia the expression and (or) the functional activity of P-glycoprotein was diminished, leading to greater hepatic and renal uptake of cyclosporine A, and renal cellular toxicity.
authors: 2-142H Katz Group Centre for Pharmacy and Health Research, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors: Dion R
authors: DR
authors: Brocks
authors: Hetal R
authors: HR
authors: Chaudhary
authors: Mohamed
authors: M
authors: Ben-Eltriki
authors: Marwa E
authors: ME
authors: Elsherbiny
authors: Ayman O S
authors: AO
authors: El-Kadi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D016572:Cyclosporine / Q000378:metabolism* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D007166:Immunosuppressive Agents; D008074:Lipoproteins; D011758:Pyrroles; D016572:Cyclosporine; D000069059:Atorvastatin