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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References
Schimidt D, Sachdeot R (2000) Oxcarbazepine for treatment of partial epilepsy: a review and recommendations for clinical use. Epilepsy Behav 1:396–405
Verrotti A, Coppola G, Parisi P, Mohn A, Chiarelli F (2010) Bone and calcium metabolism and antiepileptic drugs. Clin Neurol Neurosurg 112:1–10
Wellington K, Goa KL (2001) Oxcarbazepine: an update of its efficacy in the management of epilepsy. CNS Drugs 15:137–163
Flesch G, Francote E, Hell F, Degen PH (1992) Determination of the R-(−) and S-(+) enantiomers of the monohydroxylated metabolite of oxcarbazepine in human plasma by enantioselective high-performance liquid chromatography. J Chromatogr 581:147–151
Malátková P, Havlíková L, Wsól V (2014) The role of carbonyl reducing enzymes in oxcarbazepine in vitro metabolism in man. Chem Biol Interact 220:241–247
Tecoma ES (1999) Oxcarbazepine. Epilepsia 40(Suppl 5):37–46
Paglia G, D’apolito O, Garofalo D, Scarano C, Corso G (2007) Development and validation of a LC/MS/MS method for simultaneous quantification of oxcarbazepine and its main metabolites in human serum. J Chromatogr B 860:153–159
Schütz H, Feldmann JF, Faigle JW (1986) The metabolism of 14C-oxcarbazepine in man. Xenobiotica 16:769–778
Volosov A, Bialer M, Xiaodong S, Perucca E, Sintov A, Yagen B (2000) Simultaneous stereoselective high-performance liquid chromatographic determination of 10-hydroxycarbazepine and its metabolite carbamazepine-10,11-trans-dihydrodiol in human urine. J Chromatogr B 738:419–425
Flesch G, Czendlik C, Renard D, Lloyd P (2011) Pharmacokinetics of the monohydroxy derivative of oxcarbazepine and its enantiomers after a single intravenous dose given as racemate compared with a single oral dose of oxcarbazepine. Drug Metab Dispos 39:1103–1110
Patsalos PN, Elyas AA, Zakrzewska JM (1990) Protein binding of oxcarbazepine and its primary active metabolite, 10-hydroxycarbazepine, in patients with trigeminal neuralgia. Eur J Clin Pharmacol 39:413–415
Bring P, Ensom HH (2008) Does oxcarbazepine warrant therapeutic drug monitoring? Clin Pharmacokinet 47(12):767–778
Dickinson RG, Hooper WD, Dunstan PR, Eadie MJ (1989) First dose and steady-state pharmacokinetics of oxcarbazepine and its 10-hydroxy metabolite. Eur J Pharmacol 37:69–74
Benet LZ (2009) Predicting drug disposition via application of a biopharmaceutics drug disposition classification system. Basic Clin Pharmacol Toxicol 106:162–167
Aronica E, Sisodiya SM, Gorter JA (2012) Cerebral expression of drug transporters in epilepsy. Adv Drug Deliv Rev 64:919–929
Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75(1):13–33
Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, Zhang L, International Transporter Consortium (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 94(1):52–63
Kaur V, Garg T, Rath G, Goyal AK (2014) Therapeutic potential of nanocarrier for overcoming to P-glycoprotein. J Drug Target 7:1–12
Estudante M, Marais JG, Soveral G, Benet LZ (2013) Intestinal drug transporters: an overview. Adv Drug Deliv Rev 65(10):1340–1356
Zakeri-Milani P, Valizadeh H (2014) Intestinal transporters: enhanced absorption through P-glycoprotein-related drug interactions. Expert Opin Drug Metab Toxicol 10(6):859–871
Amin ML (2013) P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7:27–34
Varma MV, Ashokraj Y, Dey CS, Panchagnula R (2003) P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 48(4):347–359
Wahajuddin RKS, Singh SP, Taneja I (2014) Investigation of the functional role of P-glycoprotein in limiting the oral bioavailability of lumefantrine. Antimicrob Agents Chemother 58(1):489–494
Clinkers R, Smolders I, Meurs A, Ebinger G, Michotte Y (2005) Quantitative in vivo microdialysis study on the influence of multidrug transporters on the blood-brain barrier passage of oxcarbazepine: concomitant use of hippocampal monoaminases as pharmacodynamic markers for the anticonvulsant activity. J Pharmacol Exp Ther 314(2):725–731
Lemma GL, Wang Z, Hamman MA, Zaheer NA, Gorski JC, Hall SD (2006) The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates. Clin Pharmacol Ther 79(3):218–230
Antunes NJ, Wichert-Ana L, Coelho EB, Della Pasqua O, Alexandre Junior V, Takayanagui OM, Tozatto E, Lanchote VL (2013) Analysis of oxcarbazepine and the 10-hydroxycarbazepine enantiomers in plasma by LC-MS/MS : application in a pharmacokinetic study. Chirality 903:897–903
Clinical Pharmacology & Therapeutics Editorial Team (2010) Statistical guide for clinical pharmacology & threrapeutics Clin Pharmacol Ther 88:150–152
Dadashzadeha S, Javadiana B, Sadeghian S (2006) The effect of gender on the pharmacokinetics of verapamil and norverapamil in human. Biopharm Drug Dispos 27:329–334
Nunes T, Rocha J, Falcão A, Almeida L, Soares-da-Silva P (2013) Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia 54(1):108–116
Grover A, Benet LZ (2009) Effects of drug transporters on volume of distribution. AAPS J 11(2):250–261
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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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).
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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.
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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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DOI: https://doi.org/10.1007/s00228-015-1970-4