Influence of verapamil on oxcarbazepine and enantiomers of 10-hydroxycarbazepine pharmacokinetics and their relationships to cerebral perfusion in healthy volunteers

• Grant number: 12/07878-9
• Support Opportunities: Regular Research Grants
• Duration: August 01, 2012 - July 31, 2014
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Vera Lúcia Lanchote
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Eduardo Barbosa Coelho ; Lauro Wichert Ana ; Osvaldo Massaiti Takayanagui ; Veriano Alexandre Junior

Abstract

Oxcarbazepine (OXC) is a drug indicated for the treatment of partial seizures or generalized tonic-clonic seizures in adults and children. The metabolite 10-hydroxy-10 ,11-dihydro-carbazepina (MHD) has pharmacological activity, has a chiral center at position 10, with the enantiomers (S )-(+)- and R-(-)-MHD. The MHD is a substrate of P-glycoprotein (Pgp), an efflux transporter present in the blood brain barrier. Verapamil, a drug inhibitor of Pgp in various tissues including the brain. This study aims to evaluate the influence of verapamil on the pharmacokinetics of oxcarbazepine and MHD enantiomers and their relationship with cerebral perfusion in healthy volunteers. The crossover study will be conducted in three phases and will include 12 healthy volunteers, who receive one dose of the radioactive etilenodicisteína labeled with Technetium-99m (99mTc) intravenously and will be submitted to brain SPECT (Single-photon emission computed tomography). In the second phase, the volunteers will be treated during five days with 300 mg/12h oxcarbazepine. On the fifth day, serial blood samples will be collected until 12 h after oxcarbazepine administration and the SPECT will be acquired 4, 6 or 12 h after drug administration. In the third phase, the volunteers will be treated during five days with 300 mg/12h oxcarbazepine and 80 mg/8h of verapamil. On the fifth day, serial blood samples will be collected until 12 h after oxcarbazepine administration and the SPECT will be acquired 4, 6 or 12 h after drug administration. Plasma concentrations of OXC and MHD enantiomers will be evaluated by LC-MS/MS coupled with chiral stationary phase column. Pharmacokinetic analysis will be performed using the software WinNonlin and statistical tests will be conducted with the aid of GraphPad Instat (p <0.05). Population pharmacokinetics and the correlation between plasma concentrations of OXC and MHD enantiomers and SPECTs scans will be performed through the NONMEN (non-linear mixed effect model) software. (AU)