Evaluation of the Effects of Ketoconazole and Voriconazole on the Pharmacokinetics of Oxcarbazepine and Its Main Metabolite MHD in Rats by UPLC-MS-MS.
Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals.
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
Xinxin
X
Chen
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
Ermin
E
Gu
The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui 323000, China.
Shuanghu
S
Wang
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
Xiang
X
Zheng
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
Mengchun
M
Chen
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
Li
L
Wang
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
Guoxin
G
Hu
The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
Jian-ping
JP
Cai
Pharmacology Department, School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China lxd54@163.com zhouhy@wmu.edu.cn.
Hongyu
H
Zhou
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage; D001711:Biotransformation; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods / Q000592:standards; D003975:Diazepam / Q000032:analysis / Q000737:chemistry; D004338:Drug Combinations; D004347:Drug Interactions; D007654:Ketoconazole / Q000008:administration & dosage*; D057230:Limit of Detection; D008297:Male; D000078330:Oxcarbazepine; D011355:Prodrugs / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods / Q000592:standards; D065819:Voriconazole / Q000008:administration & dosage*
C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; D000935:Antifungal Agents; D004338:Drug Combinations; D011355:Prodrugs; D002220:Carbamazepine; D065819:Voriconazole; D003975:Diazepam; D007654:Ketoconazole; D000078330:Oxcarbazepine