Analysis of topiramate and its metabolites in plasma and urine of healthy subjects and patients with epilepsy by use of a novel liquid chromatography-mass spectrometry assay

被引:32
作者
Britzi, M
Soback, S
Isoherranen, N
Levy, RH
Perucca, E
Doose, DR
Maryanoff, BE
Bialer, M
机构
[1] Hebrew Univ Jerusalem, Sch Pharm, Dept Pharmaceut, Fac Med, IL-91120 Jerusalem, Israel
[2] Kimron Vet Inst, Natl Residue Control Lab, Bet Dagan, Israel
[3] Univ Washington, Sch Pharm, Seattle, WA 98195 USA
[4] Univ Pavia, Dept Internal Med & Therapeut, I-27100 Pavia, Italy
[5] Johnson & Johnson Pharmaceut Res & Dev LLC, Raritan, NJ USA
[6] Hebrew Univ Jerusalem, David R Bloom Ctr Pharm, Jerusalem, Israel
关键词
topiramate; metabolites; CNS drug; urine and plasma analysis; liquid chromatography-mass spectrometry; epileptic patients;
D O I
10.1097/00007691-200306000-00012
中图分类号
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号
1001 ;
摘要
A novel liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for quantification of topiramate (TPM) and its metabolites 10-hydroxy topiramate (10-OH-TPM), 9-hydroxy topiramate (9-OH-TPM), and 4,5-O-desisopropylidene topiramate (4,5-diol-TPM) in plasma and urine. The method uses 0.5 mL of plasma or I mL of urine that is extracted with diethyl ether and analyzed by LC-MS. Positive ion mode detection enables tandem mass spectrometric (MS/MS) identification of the aforementioned four compounds. Calibration curves of TPM, 4,5-diol-TPM, 9-OH-TPM, and 10-OH-TPM in plasma and urine were prepared and validated over the concentration range of 0.625 to 40 mug/mL using TPM-d(12) as an internal standard. Calibration curves were linear over this concentration range for TPM and its metabolites. Accuracy and precision ranged in urine from 83% to 114% and 4% to 13% (%CV), respectively, and in plasma from 82% to 108% and 6% to 13%, respectively. The applicability of the assay was evaluated by analyzing plasma samples from a healthy subject who received a single oral dose of TPM (200 mg) and urine samples from 11 patients with epilepsy treated with TPM (daily dose between 100 to 600 mg) alone or with other antiepileptic drugs. Only TPM was detected and quantified in the plasma samples, and its concentration ranged between 0.7 and 4.3 mug/mL. The concentrations of TPM and 10-OH TPM were quantifiable in all urine samples and ranged from 20 to 300 mug/mL for TPM and from 1 to 50 mug/mL for 10-OH-TPM. The metabolites 4,5-diol-TPM and 9-OH-TPM were also detected in all urine samples, but their concentrations were quantifiable only in 4 patients. An unidentified peak in the chromatograms obtained from patients' urine was attributed to 2,3-O-desisopropylidene topiramate (2,3-diol-TPM). Due to a lack of reference material of 2,3-diol TPM and the similar MS/MS spectrum with 4,5-diol-TPM, the calibration curves of 4,5-diol-TPM were used for the quantification of its isomer 2,3-diol-TPM. Based on these determinations, the apparent 2,3-diol-TPM-to-TPM concentration ratio in patients' urine ranged from 0.05 to 0.51 and the 10-OH-TPM-to-TPM ratio ranged from 0.02 to 0.17. In conclusion, a novel LC-MS method for the assay of TPM and four of its metabolites in plasma and urine was developed. Its utilization for analysis of urine samples from patients with epilepsy showed that the method was suitable for analysis of TPM and its metabolites in clinical samples. Two quantitatively significant TPM metabolites (10-OH-TPM and 2,3-diol-TPM) and two quantitatively minor metabolites (9-OH-TPM and 4,5-diol-TPM) were detected and quantified in urine samples from patients with epilepsy.
引用
收藏
页码:314 / 322
页数:9
相关论文
共 27 条
[1]  
Ben-Menachem Elinor, 1995, P1063
[2]   Comparison of topiramate concentrations in plasma and serum by fluorescence polarization immunoassay [J].
Berry, DJ ;
Patsalos, PN .
THERAPEUTIC DRUG MONITORING, 2000, 22 (04) :460-464
[3]  
Chen S, 2001, RAPID COMMUN MASS SP, V15, P159, DOI 10.1002/1097-0231(20010130)15:2<159::AID-RCM210>3.0.CO
[4]  
2-W
[5]   Topiramate therapeutic monitoring in patients with epilepsy: Effect of concomitant antiepileptic drugs [J].
Contin, M ;
Riva, R ;
Albani, F ;
Avoni, P ;
Baruzzi, A .
THERAPEUTIC DRUG MONITORING, 2002, 24 (03) :332-337
[6]   Simple and rapid liquid chromatographic-turbo ion spray mass spectrometric determination of topiramate in human plasma [J].
Contin, M ;
Riva, R ;
Albani, F ;
Baruzzi, A .
JOURNAL OF CHROMATOGRAPHY B, 2001, 761 (01) :133-137
[7]   Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug [J].
Doose, DR ;
Walker, SA ;
Gisclon, LG ;
Nayak, RK .
JOURNAL OF CLINICAL PHARMACOLOGY, 1996, 36 (10) :884-891
[8]  
Doose DR, 2002, ANTIEPILEPTIC DRUGS, V5th, P727
[9]  
Garnett WR, 2000, EPILEPSIA, V41, pS61
[10]  
Gidal BE, 2002, ANTIEPILEPTIC DRUGS, P735