The effects of calcineurin inhibitors on prostanoid synthesis: a randomized cross-over study in healthy humans

Transpl Int. 2013 Feb;26(2):131-7. doi: 10.1111/tri.12004. Epub 2012 Nov 29.

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.

Trial registration: ClinicalTrials.gov NCT00766909.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Platelets / metabolism
  • Calcineurin Inhibitors*
  • Cross-Over Studies
  • Cyclooxygenase 2 / metabolism
  • Cyclosporine / administration & dosage*
  • Double-Blind Method
  • Homeostasis
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Male
  • Middle Aged
  • Models, Biological
  • Prostaglandins I / biosynthesis*
  • Tacrolimus / administration & dosage*
  • Thromboxane A2 / metabolism
  • Young Adult

Substances

  • Calcineurin Inhibitors
  • Immunosuppressive Agents
  • Prostaglandins I
  • Thromboxane A2
  • Cyclosporine
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Tacrolimus

Associated data

  • ClinicalTrials.gov/NCT00766909