Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers
| Autor: | Maria Paula Marques, Oscar Della Pasqua, Veriano Alexandre Júnior, Eduardo Barbosa Coelho, Osvaldo Massaiti Takayanagui, Vera Lucia Lanchote, Natalícia de Jesus Antunes, Lauro Wichert-Ana, Eduardo Tozatto |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Metabolite Oxcarbazepine Pharmacology 030226 pharmacology & pharmacy 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Young Adult 0302 clinical medicine Pharmacokinetics medicine MOLÉCULA Humans Pharmacology (medical) ATP Binding Cassette Transporter Subfamily B Member 1 Volume of distribution Cross-Over Studies 010401 analytical chemistry Stereoisomerism General Medicine Carbamazepine Crossover study Healthy Volunteers 0104 chemical sciences chemistry Verapamil Anticonvulsants Female Enantiomer medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1432-1041 |
| Popis: | 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. 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. 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]. 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. |
| Databáze: | OpenAIRE |
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