Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediated metabolism

Ann Pharmacother. 2006 Jan;40(1):32-7. doi: 10.1345/aph.1G347. Epub 2005 Dec 20.


Background: Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug-drug interactions.

Objective: Using a 7-day, open-label, sequential study to determine whether lasofoxifene at steady-state concentration affects cytochrome P450-mediated drug metabolism.

Methods: 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).

Results: 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.

Conclusions: Lasofoxifene has no effect on CYP2E1- or CYP2D6-mediated drug metabolism and should not affect drugs metabolized by other cytochrome P450 isoenzymes.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Chlorzoxazone / analogs & derivatives
  • Chlorzoxazone / blood
  • Chlorzoxazone / metabolism
  • Chlorzoxazone / pharmacology
  • Chlorzoxazone / urine
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP2E1 / metabolism*
  • Cytochrome P-450 CYP2E1 Inhibitors
  • Dextromethorphan / blood
  • Dextromethorphan / pharmacology
  • Dextromethorphan / urine
  • Disorders of Excessive Somnolence / chemically induced
  • Disorders of Excessive Somnolence / epidemiology
  • Dose-Response Relationship, Drug
  • Dyspepsia / chemically induced
  • Dyspepsia / epidemiology
  • Female
  • Humans
  • Inpatients
  • Metabolic Clearance Rate
  • Middle Aged
  • Postmenopause / blood
  • Postmenopause / drug effects
  • Postmenopause / urine
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacokinetics*
  • Pyrrolidines / pharmacology
  • Retrospective Studies
  • Tetrahydronaphthalenes / metabolism
  • Tetrahydronaphthalenes / pharmacokinetics*
  • Tetrahydronaphthalenes / pharmacology
  • Time Factors


  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP2E1 Inhibitors
  • Pyrrolidines
  • Tetrahydronaphthalenes
  • 6-hydroxychlorzoxazone
  • Lasofoxifene
  • Dextromethorphan
  • Cytochrome P-450 CYP2E1
  • Cytochrome P-450 CYP2D6
  • Chlorzoxazone