Table 2.
Pharmacokinetic parameters for dextromethorphan and dextrorphan and formation clearance of the two CYP3A4 markers 3‐methoxymorphinan and 6β‐hydroxycortisol before (control) and after 13 cis RA dosing (treatment)
| Control mean (%CV) | Treatment mean (%CV) | Treatment/control GMR (90% CI) | |
|---|---|---|---|
| Dextromethorphan | |||
| Cmax (nM) | 3.59 (109) | 3.00 (104) | 0.829 (0.698–0.985) |
| AUC0–∞ (hour × nM) | 28.4 (127) | 23.3 (119) | 0.822 (0.677–0.998) |
| Cl/f (L/hour) | 3,870 (94) | 4,750 (102) | 1.23 (1.02–1.48) |
| t1/2 (hour) | 5.07 (30) | 5.03 (34) | 0.991 (0.831–1.18) |
| Dextrorphan | |||
| Cmax (nM) | 11.1 (44) | 10.8 (29) | 0.971 (0.747–1.26) |
| AUC0–∞ (hour × nM) | 51.3 (43) | 52.9 (29) | 1.03 (0.851–1.25) |
| Clf (L/hour)a | 1,840 (106) | 2,360 (121) | 1.29 (1.05–1.58) |
| AUCm/AUCp | 1.81 (78) | 2.28 (69) | 1.25 (0.998–1.57) |
| Um/Up a | 153 (70) | 173 (72) | 1.13 (0.817–1.56) |
| 3‐methoxymorphinan | |||
| Clf (L/hour)a | 22.1 (107) | 30.7 (135) | 1.39 (1.05–1.84) |
| 6β‐hydroxycortisol | |||
| Clf (mL/hour)a | 35.6 (48) | 52.8 (29) | 1.49 (0.993–2.24) |
AUC0−∞, area under the concentration‐time curve from zero to infinity; AUCm, the area under concentration curve of the metabolite; AUCp, the area under concentration curve of parent drug; %CV, percentage of coefficient of variation; CI, confidence interval; Clf, formation clearance; Cmax, maximum plasma concentration; CYP, cytochrome P450; GMR, geometric mean ratio; RA, retinoic acid; t1/2, terminal half‐life; Um, amount of metabolite excreted into urine; Up, amount of parent drug excreted into urine.
n = 7. The urinary recovery of two analytes from one subject in the 0–8 hour collection on study day 1 were determined to be outliers by the Grubb's test, and all data from this subject based on urinary measures were excluded from analysis.
All pharmacokinetic parameters are shown as geometric means with a %CV.