Influence of sepsis and age on OATP1A2 activity using rocuronium pharmacokinetics-pharmacodynamics as a model in surgical patients

• Grant number: 11/23767-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2012
• End date: December 31, 2012
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Natália Valadares de Moraes
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Rocuronium (ROC), a neuromuscular blocking agent used in surgical procedures, is eliminated primarily by biliary excretion. Its distribution to the liver, mediated by OATP1A2 hepatocellular uptake, is a derminant factor for the duration of neuromuscular blockade. The aim of this study is to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using ROC as a model drug, by evaluating its pharmacokinetics and pharmacodynamics in surgical patients ASA I-III. Adult patients without sepsis (control, n = 12), adult patients with sepsis (sepsis group, n = 12) and elderly patients without sepsis (elderly group, n = 12), all during a small to medium-sized surgical procedures will be investigate. Patients will receive individualized i.v. dose of ROC and serial blood samples will be collected up to 360 min after administration for the pharmacokinetic analysis of ROC and for the evaluation of plasma cytokines. Patients will be investigated for neuromuscular transmission using the electromyographic activity of the adductor pollicis muscle. The analysis of ROC in plasma will be developed and validated employing LC-MS/MS. The cytokines IL-1±, IL-1², IL-6, TNF-± in plasma will be analyzed by ELISA. Pharmacokinetic analysis and PK-PD analysis relating plasma concentrations of ROC with the electromyographic activity or with cytokines plasma concentration will be evaluated using the software NONMEN. The SLCO1A2 polymorphisms will be evaluated in all patients investigated. The influence of experimental sepsis in mRNA expression of OATP1A2 will be investigated in rats. The pharmacokinetic parameters Km and Vmax of ROC uptake will be assessed in human and rat sandwich-cultured hepatocytes. The Vmax and Km obtained in vitro will be used as an input into a physiologically based pharmacokinetic model (PBPK). PBPK simulations will be compared to the profiles of plasma concentration versus time observed in vivo after i.v. administration of ROC.