Increased renal clearance of rocuronium compensates for chronic loss of bile excretion, via upregulation of Oatp2

Abstract

Requirement for rocuronium upon surgery changes only minimally in patients with end-stage liver diseases. Our study consisted of both human and rat studies to explore the reason. The reduction rate of rocuronium infusion required to maintain neuromuscular blockade during the anhepatic phase (relative to paleohepatic phase) was examined in 16 children with congenital biliary atresia receiving orthotopic liver transplantation. Pharmacodynamics and pharmacokinetics of rocuronium were studied based on BDL rats. The role of increased Oatp2 and decrease Oatp1 expressions in renal compensation were explored. The reduction of rocuronium requirements significantly decreased in obstructively jaundiced children (24 +/- 9 vs. 39 +/- 11%). TOF50 in BDL rats was increased by functional removal of the kidneys but not the liver, and the percentage of rocuronium excretion through urine increased (20.3 +/- 6.9 vs. 8.6 +/- 1.8%), while that decreased through bile in 28d-BDL compared with control group. However, this enhanced renal secretion for rocuronium was eliminated by Oatp2 knock-down, rather than Oatp1 overexpression (28-d BDL vs. Oatp1-ShRNA or Oatp2-ShRNA, 20.3 +/- 6.9 vs. 17.0 +/- 6.6 or 9.3 +/- 3.2%). Upon chronic/sub-chronic loss of bile excretion, rocuronium clearance via the kidneys is enhanced, by Oatp2 up-regulation.