dextromethorphan and Disorders-of-Excessive-Somnolence

Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug-drug interactions.. Using a 7-day, open-label, sequential study to determine whether lasofoxifene at steady-state concentration affects cytochrome P450-mediated drug metabolism.. Lasofoxifene was tested in 18 postmenopausal women with probe drugs for CYP2E1 and CYP2D6. Changes in CYP2E1 metabolism were measured by the formation clearance of 6-hydroxychlorzoxazone (6-OHCLZ; Cl(f,6-OHCLZ)) following a 250 mg dose of chlorzoxazone in the absence (day 1) and presence (day 6) of lasofoxifene. Changes in the dextromethorphan/dextrorphan urine metabolic ratio (MRDX) measured the effect on CYP2D6 metabolism following a 30 mg dose of dextromethorphan in the absence and presence of lasofoxifene (days 2 and 7).. Steady-state lasofoxifene did not affect the formation clearance of 6-OHCLZ or the urinary MRDX. For 6-OHCLZ, the lower boundary (87.12%) of the 90% confidence interval for the ratio (day 6/day 1) of Cl(f,6-OHCLZ) was well above the clinically acceptable ratio of 60%. Both the individual and group mean Cl(f,6-OHCLZ) values were comparable in the absence and presence of lasofoxifene. For MRDX, the upper boundary (129.37%) of the 90% confidence interval for the ratio (day 7/day 2) of MRDX was well below the stipulated ratio of 200%. The individual and mean MRDX values were comparable in the absence and presence of lasofoxifene. Lasofoxifene was well tolerated; adverse events were mild and transient.. Lasofoxifene has no effect on CYP2E1- or CYP2D6-mediated drug metabolism and should not affect drugs metabolized by other cytochrome P450 isoenzymes.

Topics: Administration, Oral; Chlorzoxazone; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Dextromethorphan; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Dyspepsia; Female; Humans; Inpatients; Metabolic Clearance Rate; Middle Aged; Postmenopause; Pyrrolidines; Retrospective Studies; Tetrahydronaphthalenes; Time Factors