title: An underlying role for hepatobiliary dysfunction in cyclosporine A nephrotoxicity.
abstract: Renal-derived cysteinyl leukotrienes (cysLT), such as leukotrienes C(4) (LTC(4)) and D(4) (LTD(4)) are thought to mediate acute and chronic cyclosporine A (CSA) nephrotoxicity. However, whole-body cysLT elimination is regulated primarily by hepatobiliary excretion. Since CSA is known to alter hepatobiliary function, the effects of CSA on whole-body cysLT elimination were investigated in vivo, with respect to hepatobiliary and renal function. Male rats were anesthetized and cannulated (jugular vein, bile duct, and urinary bladder). A tracer dose of tritiated LTC(4) ((3)H-LTC(4)) was administered systemically (i.v.) immediately following vehicle and then 90 min later after vehicle or CSA. In vehicle/vehicle controls, hepatobiliary (3)H-cysLT elimination predominated over renal elimination without altering glomerular filtration rate (GFR), bile flow, and urine production. (3)H-cysLT elimination kinetics were comparable between each 90 min collection period. In vehicle/CSA-treated rats, an acutely nephrotoxic dose of CSA (20 mg/kg, i.v.) reduced urine flow 74+/-9% and caused a transient reduction in GFR, while total bile flow decreased 40+/-13%. Hepatobiliary and renal (3)H-cysLT elimination was also impaired 59+/-5 and 61+/-18%, respectively. In contrast, a non-nephrotoxic dose (2 mg/kg i.v.) increased renal (3)H-cysLT elimination due to impaired hepatobiliary elimination without affecting GFR, bile flow or urine production. Both doses caused (3)H-cysLT retention in hepatic and renal tissue. These findings demonstrate that CSA alters whole-body handling of cysLT by disrupting hepatobiliary cysLT elimination. This disruption leads to increased renal exposure to systemically derived cysLT and renal cysLT tissue retention. Renal exposure to and accumulation of systemically derived cysLT products may be underlying factors in CSA nephrotoxicity.
authors.affiliation: Pfizer Global Research and Development, Drug Safety Research and Development, Groton/New London Laboratories, MS8274-1229, Investigative Toxicology, Eastern Point Road, Groton, CT 06340-8014, USA. michael.d.aleo@pfizer.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Aleo
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Doshna
authors.forename: Carol A
authors.initials: CA
authors.lastname: Fritz
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013931:Thromboxanes / Q000096:biosynthesis*
chemical_list: D007166:Immunosuppressive Agents; D013931:Thromboxanes; D017997:Leukotriene C4; D016572:Cyclosporine