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And Dextrorphan Glucuronidation in a French Population International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 31 No. 8 - 1993 (392-398) Dextromethorphan 0-demethylation and dextrorphan glucuronidation in a French population J.-C. DUCH~, V. QUEROL-FERRER, J. BARR& M. MBSANGEAU and J.-P TILLEMENT Laboratoire Hospitalo-Universitaire de Pharmacologic, Centre Hospitalier Intercommunal, CrPteil Cedex, France Abstract. The dextromethorphan (DMP) 0-demethylation and the dextrorphan (DRP) glucuronidation distributions were studied in 120 French Caucasian subjects. After a single 25 mg DMP oral administration, DMP, free and total DRP concentrations were measured in Sh-urine collection, using an HPLC technique with fluorescent detection. The DMP and free DRP concentrations ratio, in log form, was used to estimate the oxidative demethylation phenotype of the subjects. Two different populations were found. The first one consisted of the extensive metabolizers (90.8%, 95% confidence interval from 85.6 to 95.9%) and the second one consisted of poor metabolizers (9.2%, 95% confidence interval from 4.0 to 14.4%). The antimode value of the distribution was estimated at approximately 0.7 corresponding to a ratio of 5. Moreover, this ratio was compared to the DMP and total DRP concentrations ratio, usually defined to DMP 0-demethylation phenotyping. On the other hand, the glucuronide DRP concentration was calculated by subtracting the free DRP concentration from the total DRP concentration. Consequently, the free DRP and glucuronide DRP concentrations ratio was also used to estimate the DRP glucuronidation in the present population. This ratio in log form reflected the UDP-glucuronyltransferase(s) capacity(ies). This log ratio appeared to be normally distributed in the population studied. These results show that log DMP/free DRP ratio can be used, as well as log DMP/total DRP ratio, to determine the oxidative phenotype of subjects and that the DRP conjugation does not exhibit any apparent genetic polymorphism. Key words: dextromethorphan - free and total dextrorphan - glucuronide dextrorphan - genetic polymorphism - HPLC technique Introduction Since this cytochrome P45O isozyme is also implicated in the debrisoquine 4-hydroxylation Dextromethorphan (DMP) is a widely used anti- [Mahgoub et al. 19771 and in the sparteine reduction tussive drug, displaying no narcotic effect. Its [Eichelbaum et al. 19791, DMP has been proposed as a metabolism (Figure 1) is under genetic control probe for the cytochrome P450IID6 activity in [Schmid et al. 1985, Kiipfer et al. 19861. It is mainly human. The absence or the presence of the enzyme is metabolized to DRP, by 0-demethylation, involv- defined as poor or extensive metabolizer, respectively. ing the cytochrome P4501ID6 isozyme, which is For this purpose, Larrey et al. [1987] recently then conjugated by UDP-glucuronosyltransferase(s) reported an incidence of about 3.9% of poor (UDP-GT[s]). The formation of 3-methoxymor- metabolizers in a French population. In this study, phinane by N-demethylation represents a minor route 120 healthy subjects were investigated to determine of DMP metabolism [Kiipfer et al. 19861. the log urinary metabolic ratio DMP/free DRP (log DMPADRP), compared with the log DMP/total DRP (log DMP/tDRP), for the DMP 0-demethylation activity. On the other hand, the DRP glucuronidation Received March 26, 1993. was evaluated using the log urinary free DRP/ Reprint requests to Dr. J.-C. DuchC, Laboratoire Hospitalo- glucuronide DRP ratio (log fDRP/gDRP) in order to Universitaire de Pharmacologic, Cenrre Hospitalier Intercom- search for a possible genetic polymorphism of UDP- munal, 40 Avenue de Verdun, F-94010 Crheil Cedex, France. GT(s). Dextromethorphan 0-demethylation and dextrorphan glucuronidation CHJO . I Dextromethorphan . 7 N-CH, -d \ P450 llD6 \ N-Demethylase / HO CHoO / Glucuronosyl- transferase 1 GLU-0 N-H N-CH, Fig. 1 Metabolism of dextro- 3-Hydroxymorphinan merhorphan in man Glucuronide Subjects and method r?-otocol Subjects The subjects were given orally 25 mg of dex- tromethorphan hydrobromide at 8:00 h and the urine One hundred and twenty French Caucasian sub- was collected over an 8-h period. Total urine volumes jects (79 men and 41 women) gave their written were noted and the aliquots (2 x 5 ml) were stored at consents and took part in the study. Their ages ranged -20” C until drug analysis. The logarithm of the from 25 to 75 years. None of the subjects was taking metabolic ratios DMP/fDRP and fDRP/gDRP was any medication at the time of the study and their used to assess the 0-demethylation of DMP and the alcohol and tobacco consumption were moderate. glucuronidation of DRP, respectively. The DMP and 394 DuchP, QuProl-Ferrer, Barre’, Mksangeau and Tillement free/total DRP assays were performed by using an The analysis was performed at room temperature HPLC technique with fluorescent detection. Hy- using a Hypersil ODS reversed-phase column drolysis of DMP conjugates and extraction of DMP (250 mmx4.5 mm ID, 5 pm particle size). The and DRP were performed as described by East and mobile phase was composed of 75% 0.01 M potas- Dye [1985] and Silvasti et al. [1987], with some sium dihydrogenophosphate with 1% triethylamine modifications. Briefly, 500 pl or 100 ~1 of urine were pH 3 (using orthophosphoric acid) - 3% tetrahy- used and 4 ~18 (DMP and fDRP determination) or drofuran - 22% acetonitrile. The flow-rate was 2 ml/ 20 pg (tDRP determination) diphenhydramin were min. The detection of the compounds was performed added as the internal standard. The compounds were using a Schoeffel FS 970 fluorescence detector equip- extracted with 6 ml pentane containing 2% triethy- ped with a 200 nm excitation filter and no emission lamine, and after centrifugation and evaporation to cut-off filter. Under these chromatographic condi- dryness, the residue was dissolved in 250 ~.tl1% acetic tions, the retention times of DRP, DMP and internal acid and 50 ~1 were injected into the column. standard were 3, 8 and 10 minutes, respectively. The calibration curves of DMP and DRP were linear over concentrations ranging from 0.1 to 1 ug/ml and from Number of subjects 0.1 to 10 pg/ml, respectively. The between-run varia- 50, tion ranges from 7.8 to 13% for DMP and from 8.2 to 11.9% for DRP. The limits of quantification were 40 1 0.026 and 0.032 rig/ml for DRP and DMP, respec- tively. 30 20 Statistics 10 Frequency histogram and probit plots were con- r-l structed for the log DMP/fDRP, log DMP/tDRP and ” -2 -1.5 -1 -0.5 0 0.5 1 1.5 for the log fDRP/gDRI? The Spearman rank correla- log DMP/fDRP tion coefficient was also used to compare the relation- Ftg.2a Frequency distribution of the log DMP/fDRP for ship between the log DMP/fDRP and log DMP/tDRP 0-demethylation in 120 subjects ratios. Probit 3 I + 2 + I i l -1 . / +t+* + -2 . t + + I -2 -1.5 -1 -5 0 .5 1 1.5 2 2.5 Fig. 2b Problt plot representation log DMP/fDRP of the log DMP/fDKP , Dextromethorphan 0-demethylation and dextrorphan glucrrronidation 395 t t Results a normal distribution (Figure 5a) supported by a straight line in the probit plot representation with I The frequency distribution of the log DMPI values ranging from -2 to -0.85 (Figure 5 b). The DRP fDRP for 0-demethylation in the 120 subjects exhi- glucuronidation capacity, defined as the glucuronide bited an asymmetrical distribution (Figure 2 a). In DRP and total DRP concentrations ratio, of all the addition, the upper part of the probit plot representa- subjects varied from 87 to 99%. tion was steep (Figure 2 b), demonstrating a slope disruption of the theoretical straight line (for a gaus- Sian distribution) which confirmed the bimodal dis- Discussion tribution of the DMP 0-demethylation [Schmid et al. 1985, Kiipfer et al. 19861.Eleven subjects (9.2%) were Our results for the DMP 0-demethylation, found to be poor metabolizers of DMP and an using both log DMP/fDRP or log DMP/tDRP ratios, antimode could be estimated at 0.7 which corresponds are in agreement with those previously reported to a DMP/fDRP ratio of 5. The frequency distribu- tion of the log DMP/tDRP ratio and the probit plot representation are shown in Figures 3a and 3 b, respectively. Using this last metabolic ratio, we have Number of subjects also found an asymmetrical distribution with an =Ot antimode around -0.5 corresponding to a DMP/tDRP ratio of 0.3 as previously described by Schmid et al. 40 I- / [1985] and Kiipfer et al. [1986]. A correlation plot between log DMPADRP and log DMP/tDRP ratios 30 showed that these two distributions are similar since all the points were drawn on the same straight line 20 (Figure 4). The Spearman rank coefficient was 0.937, demonstrating a very strong relationship between the 10 two ratios studied. This result showed that the log DMP/fDRP ratio could be used as well as the log n DMP/tDRP ratio to appreciate the genetic pofy- -3.5 -2.5 -1.5 -0.5 0.5 morphism of the DMP 0-demethylation. log DMP/tDRP Moreover, the frequency distribution of the log Fig.3u Frequency distribution of the log DMP/tDRP for fDRP/gDRP ratio for DRP-glucuronidation followed 0-demethvlation in 120 subjects Probit 3- 2 -. I++ + *+’ ++++ 1 .* *++*+ ++* l * 0 .. -1 . + ++ -2 + + t I Fig. 3 b Probit plot representation -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0 .5 1 of the log DMP/tDRP log DMP/tDRP 396 Duche, Que’rol-Ferrer, Barr& Mesangeau and Tillement log DMPADRP 2.5 1.5 1 .5 0 -. 5 -1 -1.5 -2 Fig, 4 A correlarion plot for uri- -3.5 -3 -2.5 -2 -1.5 -1 -.5 0 .5 1 nary log DMP/fDRP and 1% log DMP/tDRP DMPltDRP ratios in 120 subjects Number of subiects Recently, Hou et al.
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