Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers
| العنوان: | Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers |
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| المؤلفون: | 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 |
| المصدر: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1432-1041 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::79c6e173a95b2c3f4881a7fa17961cfeTest https://pubmed.ncbi.nlm.nih.gov/26514967Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....79c6e173a95b2c3f4881a7fa17961cfe |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14321041 |
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