Novel single-point plasma or saliva dextromethorphan method for determining CYP2D6 activity.
O-Demethylation of dextromethorphan co-segregates with 4-hydroxylation of debrisoquin and is used for CYP2D6 phenotyping. In most previous studies, 8-h urinary samples were collected for determining the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan molar ratio). In addition, a salivary sampling at 3 h had been suggested for the phenotyping. To evaluate the repeatability and validity of previously reported and other potential phenotyping methods, we determined the metabolic ratios from urine samples (for various intervals), or from plasma or saliva (at varying time points) 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 period I and period II, 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 period I and period II, respectively, with a 2-week washout period. Dextromethorphan and dextrorphan were assayed by high-performance liquid chromatography. In the single-dose study, most metabolic ratios revealed good repeatabilities for the two periods (paired t test). The metabolic ratio from urine collected for 4 h, 6 h, 8 h or 12 h from plasma at any time between 1 h and 5 h or at 8 h, or from saliva at 2 h or 6 h, could reflect that from 0- to 24-h urine or AUCinfinity. In the multiple-dose study, all metabolic ratios revealed good repeatabilities. The plasma metabolic ratio at any time between 0.5 h and 10 h or the saliva metabolic ratio at any time between 3 h and 12 h, but not the urine metabolic ratio from any interval, could predict the metabolic ratio from ACUSStau. The 2 h, 3 h, 4 h or 5 h plasma metabolic ratio and 6 h saliva metabolic ratios after a single dose correlated significantly with their corresponding multiple-dose metabolic ratio (r > 0.8, P < .05). In conclusion, the plasma sample at 2 h, 3 h, 4 h or 5 h or the saliva sample at 6 h in either the single immediate-release (15 mg) or the multiple controlled-release dose (60 mg) procedure could be used for determining the dextromethorphan metabolic ratio.
Hu
O Y
OY
Pharmaceutical Research Institute and School of Pharmacy, Taipei and Laboratory of Biological Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan, Republic of China.
Tang
H S
HS
Lane
H Y
HY
Chang
W H
WH
Hu
T M
TM
D000328:Adult; D000996:Antitussive Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000032:analysis* / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D003917:Dextrorphan / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D006801:Humans; D008297:Male; D010641:Phenotype; D012463:Saliva / Q000201:enzymology
D000996:Antitussive Agents; D018691:Excitatory Amino Acid Antagonists; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6