title: The effects of calcineurin inhibitors on prostanoid synthesis: a randomized cross-over study in healthy humans.
abstract: The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus (Tac) are implicated in post-transplant complications such as cardiovascular morbidity. Prostanoids are fatty acid-derived compounds essential for controlling cardiovascular homeostasis. We tested the hypothesis that CNIs suppress cyclooxygenase (COX)-2-derived prostacyclin (PGI) and increase thromboxane synthesis in humans. Ten healthy men underwent 5-h infusions of CsA, Tac, and saline in a randomized, double-blind, cross-over study. Blood and urine samples were collected before and after the infusion of each drug/saline, to measure PGI and thromboxane metabolites. CsA decreased whole-blood COX-2 activity by 39% (P = 0.05) and basal plasma 6-keto-PGF(1α)  levels by 31%, only nonsignificantly. Urine excretion of PGI-M and TxB(2)  did not change significantly after CsA infusion. Tac decreased TxB(2)  in the COX-1 ex vivo assay by 30% (P = 0.03), while no changes were seen in urinary levels of PGI-M or TxB(2) . Urinary TxB(2)  excretion was 15% lower after saline infusion (P = 0.03). These within-treatment differences in prostanoid synthesis did not differ significantly between the treatments (anova). Mean blood levels of CNIs were 486 μg/l for CsA and 12.8 μg/l for Tac. Clinically relevant doses of CsA and Tac induce acute differential changes in prostanoid levels in healthy human subjects. CsA suppresses COX-2 activity, while Tac decreases platelet activity.
authors.affiliation: Department of Nephrology, Aarhus University Hospital, Skejby, Aarhus, Denmark. doc.aygen@gmail.com
authors.forename: Lara Aygen
authors.initials: LA
authors.lastname: Øzbay
authors.forename: Jane
authors.initials: J
authors.lastname: Stubbe
authors.forename: Bente
authors.initials: B
authors.lastname: Jespersen
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000378:metabolism; D065095:Calcineurin Inhibitors; D018592:Cross-Over Studies; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage*; D004311:Double-Blind Method; D006706:Homeostasis; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D044062:Prostaglandins I / Q000096:biosynthesis*; D016559:Tacrolimus / Q000008:administration & dosage*; D013928:Thromboxane A2 / Q000378:metabolism; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D044062:Prostaglandins I; D013928:Thromboxane A2; D016572:Cyclosporine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D016559:Tacrolimus