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Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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 (AUC0–12 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 AUC0–12 [R-(−)-MHD: 23.79 vs 26.19 μg h/mL and S-(+)-MHD: 97.87 vs 108.35 μg h/mL].

Conclusion

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.

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Acknowledgments

The authors are grateful to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Apoio ao Ensino, Pesquisa e Assistência, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA) for the financial support.

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Authors and Affiliations

  1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Natalícia de Jesus Antunes, Eduardo Tozatto, Maria Paula Marques & Vera Lucia Lanchote

  2. Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Lauro Wichert-Ana & Eduardo Barbosa Coelho

  3. Division of Pharmacology, School of Science, University of Leiden, Leiden, The Netherlands

    Oscar Della Pasqua

  4. Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Veriano Alexandre Junior

  5. Departamento de Neurologia, Psiquiatria e Psicologia Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Osvaldo Massaiti Takayanagui

Authors
  1. Natalícia de Jesus Antunes
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  2. Lauro Wichert-Ana
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  4. Oscar Della Pasqua
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  5. Veriano Alexandre Junior
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  8. Maria Paula Marques
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  9. Vera Lucia Lanchote
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Corresponding author

Correspondence to Vera Lucia Lanchote.

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Financial support

This study was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA).

Ethics approval

The project was approved by the Ethics Committees of the School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, and of the University Hospital of the Ribeirão Preto School of Medicine, University of São Paulo (Protocol No. 214). All subjects signed the free informed consent form.

Additional information

Chemical compounds studied in this article Oxcarbazepine (PubChem CID: 34312); 10-hydroxycarbazepine (PubChem CID: 114709); verapamil hydrochloride (PubChem CID: 62969)

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de Jesus Antunes, N., Wichert-Ana, L., Coelho, E.B. et al. Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers. Eur J Clin Pharmacol 72, 195–201 (2016). https://doi.org/10.1007/s00228-015-1970-4

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