Single-point plasma or urine dextromethorphan method for determining CYP3A activity.
Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Also dextromethorphan is N-demethylated in vivo to 3-methoxymorphinan by human CYP3A4/5. The metabolic ratio (MR) of dextromethorphan/3-methoxymorphinan in plasma, saliva and urinary were examined as a possible in vivo probe of CYP3A activity. In limited previous studies, 4 h urinary samples were collected for determining the MR. To evaluate the repeatability and validity of previously reported and other potential phenotyping methods, the MR from urine samples (at various intervals), from plasma and from saliva (at varying time points) were determined after repetitive single doses of immediate-release or repetitive multiple doses of controlled-release dextromethorphan preparations. For the single-dose study, each of 12 subjects received 15 mg of immediate-release dextromethorphan in periods II and I, respectively, with a 1 week washout period. For the multiple dose study, each of 16 subjects received 60 mg controlled release dextromethorphan twice daily for 5 days in periods I and II, respectively, with a 2 week washout period. Dextromethorphan and 3-methoxymorphinan are assayed by high-performance liquid chromatography. In the single-dose study, all of the urine MR revealed good repeatabilities for the periods (paired t-test). The urine MR at any time interval of 0-6 h, 0-8 h and 0-12 h correlated significantly with the MR from 0-24 h urine (r>0.8, p<0.05). In the multiple-dose study, all MR revealed good repeatabilities for the two periods (paired t-test). The plasma MR at any time between 0.5 h and 12 h, the saliva MR at 12 h and the urine MR at any interval between 0-2 h, 0-4 h, 0-6 h, 0-8 h, 0-12 h and 0-24 h could predict the MR from AUCtau(ss). In conclusion, the urine sample as 0-6 h, 0-8 h or 0-12 h in the single immediate-release dose (15 mg) or in the multiple controlled-release dose (60 mg) procedure, the saliva sample at 12 h, the urine sample at 0-2 h, 0-4 h, 0-6 h, 0-8 h, 0-12 h, 0-24 h or all plasma-sampling points 0.5-12 h could be used as the dextromethorphan MR for determining the CYP3A activity.
Kuo
Benjamin Pei-Chung
BP
Graduate Institute of Life Sciences, National Defense Medical Center and Academy Sinica, Taipei, Taiwan, ROC.
Hu
Oliver Yoa-Pu
OY
Hsiong
Cheng-Huei
CH
Pao
Li-Heng
LH
Chen
Ting-Shien
TS
Hung
Chi-Feng
CF
D000284:Administration, Oral; D000328:Adult; D000996:Antitussive Agents / Q000032:analysis* / Q000097:blood / Q000652:urine; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003692:Delayed-Action Preparations; D003915:Dextromethorphan / Q000031:analogs & derivatives* / Q000032:analysis* / Q000097:blood / Q000378:metabolism / Q000652:urine; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype; D012463:Saliva / Q000378:metabolism
D000996:Antitussive Agents; D003692:Delayed-Action Preparations; C028657:3-methoxymorphinan; D003915:Dextromethorphan; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating