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

• Grant number: 13/14730-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2014
• End date: January 31, 2016
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Natália Valadares de Moraes
• Grantee: Natália Valadares de Moraes
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• City of the host institution: Araraquara

Abstract

Clinical pharmacology research has focused for many years on phase I and phase II metabolism to predict the elimination of xenobiotics. However, in the last decade, clinical pharmacology recognized that the kinetic disposition of drugs is also highly dependent on the expression and activity of transporting proteins. The organic anion transporting polypeptide 1A2 (OATP1A2) expressed in the apical membrane of colangiocytes regulates uptake of endogenous compounds and a variety of drugs in clinical use. Rocuronium (ROC), a neuromuscular blocker used in surgical procedures, is primarily eliminated by biliary excretion. Its distribution to the liver, which is dependent on the OATP1A2 uptake, is a determinant factor for the duration of neuromuscular blockade. Age and release of cytokines during inflammation and infection processes of sepsis can alter expression of SLCO1A2 gene, encoding OATP1A2. The objective of the study is to evaluate the influence of age and sepsis in in vivo activity of OATP1A2 using ROC as model drug and evaluating its pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Adult patients without sepsis (Control group, n = 12), adult patients with sepsis (Sepsis group, n = 12) and elderly patients without sepsis (Elderly group, n = 12) during of small to medium-sized surgical procedures will be investigated. Pharmacokinetic analysis and PK-PD relating plasma concentrations of ROC with the electromyographic activity or plasma cytokines IL-1±, IL-1², IL-6, TNF-± will be investigated. The influence of experimental sepsis in OATP1A2 mRNA expression will be investigated in rats. Based on the results of pharmacokinetic parameters and PK-PD parameters of ROC we will be able to assess the need for dose adjustment in elderly patients and in patients with sepsis under surgical procedures. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

HAPP, MIRIAM S. R.; PIPPA, LEANDRO F.; LAURETTI, GABRIELA R.; GEBHART, ANTHONY R.; WEINDL, GUENTHER; AZEREDO, FRANCINE J.; VOZMEDIANO, VALVANERA; SCHMIDT, STEPHAN; DE MORAES, NATALIA V.. Unravelling sources of variability on rocuronium pharmacokinetics: Implications for prolonged recovery in older patients. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, v. N/A, p. 13-pg., 2025-01-09. (13/14730-0)

COSTA, A. C. C.; COELHO, E. B.; LANCHOTE, V. L.; CORREIA, B. V.; ABUMANSUR, J. T.; LAURETTI, G. R.; DE MORAES, N. V.. The SLCO1A2-189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, v. 73, n. 8, p. 957-963, AUG 2017. (13/14730-0)