In-vivo indices of CYP2D6 activity:: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma

被引:35
作者
Chládek, J
Zimová, G
Beránek, M
Martínková, J
机构
[1] Charles Univ, Fac Med, Dept Pharmacol, Hradec Kralove, Czech Republic
[2] Charles Univ, Fac Hosp, Dept Clin Biochem & Diagnost, Hradec Kralove 50002, Czech Republic
关键词
D O I
10.1007/s002280000218
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Objectives: Dextromethorpan (DM) is widely used as a probe drug to assess in vivo the activity of the cytochrome P450 2D6 (CYP2D6). The aim of the study was to compare metabolic ratios (MRs) of DM to dextrorphan (DEX) in plasma and urine. We examined, separately in urine and plasma, the relationships between the MRs which are based on DEX and those involving the sum of DEX and a secondary metabolite hydroxymorphinan (HM). Furthermore, we compared the MRs in plasma obtained with and without hydrolysis of DEX glucuronides. Methods: Concentrations of DM and metabolites in urine and plasma were determined by HPLC after a single oral dose of 30 mg DM hydrobromide to 101 healthy Caucasian subjects. Urine was collected over the time interval 0-4 h after the dose and plasma was obtained from 95 subjects 3 h after administration. Results. Six subjects (5.9%) were of poor metaboliser (PM) phenotype (urinary DM:DEX ratio >0.3). A good correlation (r(2) = 0.777, P < 0.00001) was observed between the metabolic ratios of DM:DEX in plasma and urine. There was an excellent correlation, both in plasma and urine, between the log-transformed ratios of DM:DEX and of DM to the sum of molar concentrations of DEX and HM (r(2) > 0.996, P < 0.00001). Plasma samples of 89 subjects (83 EM and 6 PM) were analyzed without deconjugation of DEX glucuronide also. The correlation between the plasma ratios of DM:DEX glucuronide (r(2) = 0.793, P < 0.00001) was comparable to that reported by other authors on urine. Conclusion. In healthy Caucasian subjects, the MRs of DM to DEX in plasma obtained at 3 h correlated reasonably well with those in urine collected over the time interval 0-4 h after the dose. Nevertheless, repeatability of this plasma index should be determined before its wide use can be recommended. Finally, the interindividual variation in DEX metabolism to HM (catalyzed by CYP3A) contributes only minimally to the interindividual variability of the MRs.
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页码:651 / 657
页数:7
相关论文
共 32 条
[21]   Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: Characterization of 48 mutations and 53 alleles, their frequencies and evolution [J].
Marez, D ;
Legrand, M ;
Sabbagh, N ;
LoGuidice, JM ;
Spire, C ;
Lafitte, JJ ;
Meyer, UA ;
Broly, F .
PHARMACOGENETICS, 1997, 7 (03) :193-202
[22]   DEXTROMETHORPHAN - POLYMORPHIC SERUM PATTERN OF THE O-DEMETHYLATED AND DIDEMETHYLATED METABOLITES IN MAN [J].
MORTIMER, O ;
LINDSTROM, B ;
LAURELL, H ;
BERGMAN, U ;
RANE, A .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1989, 27 (02) :223-227
[23]   In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity [J].
Rostami-Hodjegan, A ;
Kroemer, HK ;
Tucker, GT .
PHARMACOGENETICS, 1999, 9 (03) :277-286
[24]  
Sachse C, 1997, AM J HUM GENET, V60, P284
[25]   POLYMORPHIC DEXTROMETHORPHAN METABOLISM - CO-SEGREGATION OF OXIDATIVE O-DEMETHYLATION WITH DEBRISOQUIN HYDROXYLATION [J].
SCHMID, B ;
BIRCHER, J ;
PREISIG, R ;
KUPFER, A .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1985, 38 (06) :618-624
[26]  
Schmider J, 1997, BIOPHARM DRUG DISPOS, V18, P227, DOI 10.1002/(SICI)1099-081X(199704)18:3<227::AID-BDD18>3.0.CO
[27]  
2-L
[28]   Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping [J].
Streetman, DS ;
Ellis, RE ;
Nafziger, AN ;
Leeder, JS ;
Gaedigk, A ;
Gotschall, R ;
Kearns, GL ;
Bertino, JS .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1999, 66 (05) :535-541
[29]   Assessment of CYP2D6 and CY2C19 activity in vivo in humans:: A cocktail study with dextromethorphan and chloroguanide alone and in combination [J].
Tennezé, L ;
Verstuyft, C ;
Becquemont, L ;
Poirier, JM ;
Wilkinson, GR ;
Funck-Brentano, C .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1999, 66 (06) :582-588
[30]  
VINCENTVIRY M, 1991, CLIN CHEM, V37, P327