J Chládek1, G Zimová, M Beránek, J Martínková. 1. Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic. chladekj@1fhk.cuni.cz
Abstract
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 (r2 = 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 (r2 > 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 based on unconjugated DEX and those involving glucuronide (r2 = 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.
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 (r2 = 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 (r2 > 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 based on unconjugated DEX and those involving glucuronide (r2 = 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.
Authors: Samanta Yubero-Lahoz; Ricardo Pardo; Magí Farré; Brian O'Mahony; Marta Torrens; Cristina Mustata; Clara Pérez-Mañá; Marcel Lí Carbó; Rafael de la Torre Journal: Clin Pharmacokinet Date: 2011-05 Impact factor: 6.447
Authors: M R Shiran; J Chowdry; A Rostami-Hodjegan; S W Ellis; M S Lennard; M Z Iqbal; O Lagundoye; N Seivewright; G T Tucker Journal: Br J Clin Pharmacol Date: 2003-08 Impact factor: 4.335