title: Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers.
abstract: OBJECTIVE
  Oxcarbazepine (OXC), a second-generation antiepileptic, and its chiral metabolite 10-hydroxycarbazepine (MHD) are substrates of P-glycoprotein, which can be inhibited by verapamil. This study evaluated the influence of verapamil on the pharmacokinetics of OXC and MHD enantiomers in healthy volunteers.
  
  
  METHODS
  Healthy volunteers (n = 12) on occasion O (OXC monotherapy) received 300 mg OXC/12 h for 5 days, and on the O + V occasion (treatment with OXC  + verapamil), they received 300 mg OXC/12 h and 80 mg verapamil/8 h for 5 days. Blood samples were collected over a period of 12 h. Total and free plasma concentrations of OXC and the MHD enantiomers were evaluated by LC-MS/MS. Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program.
  
  
  RESULTS
  The kinetic disposition of MHD was enantioselective with plasma accumulation (AUC(0-12) S-(+)/R-(-) ratio of 4.38) and lower fraction unbound (0.37 vs 0.42) of the S-(+)-MHD enantiomer. Treatment with verapamil reduced the OXC mean residence time (4.91 vs 4.20 h) and apparent volume of distribution (4.72 vs 3.15 L/kg). Verapamil also increased for both MHD enantiomers C max total [R-(-)-MHD: 2.65 vs 2.98 μg/mL and S-(+)-MHD: 10.15 vs 11.60 μg/mL], C average [R-(-)-MHD: 1.98 vs 2.18 μg/mL and S-(+)-MHD: 8.10 vs 8.83 μg/mL], and AUC(0-12) [R-(-)-MHD: 23.79 vs 26.19 μg h/mL and S-(+)-MHD: 97.87 vs 108.35 μg h/mL].
  
  
  CONCLUSIONS
  Verapamil increased the AUC values of both MDH enantiomers, which is probably related to the inhibition of intestinal P-glycoprotein. Considering that the exposure of both MHD enantiomers was increased in only 10 %, no OXC dose adjustment could be recommended in the situation of verapamil coadministration.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Natalícia de Jesus
authors.initials: Nde J
authors.lastname: Antunes
authors.affiliation: Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Lauro
authors.initials: L
authors.lastname: Wichert-Ana
authors.affiliation: Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.affiliation: Division of Pharmacology, School of Science, University of Leiden, Leiden, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
authors.affiliation: Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Veriano
authors.initials: V
authors.lastname: Alexandre Junior
authors.affiliation: Departamento de Neurologia, Psiquiatria e Psicologia Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Osvaldo Massaiti
authors.initials: OM
authors.lastname: Takayanagui
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tozatto
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. lanchote@fcfrp.usp.br.
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D000078330:Oxcarbazepine; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C039775:10,11-dihydro-10-hydroxycarbamazepine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002220:Carbamazepine; D014700:Verapamil; D000078330:Oxcarbazepine
keywords: 10-hydroxycarbazepine; Enantiomers; Oxcarbazepine; P-glycoprotein; Pharmacokinetics