Moller Robert A, Fisher Jeannine M, Taylor Ann E, Kolluri Sheela, Gardner Mark J, Obach R Scott, Walsky Robert L
Pfizer Worldwide Clinical Development, New York, NY 10017-5755, USA.
Ann Pharmacother. 2006 Jan;40(1):32-7. doi: 10.1345/aph.1G347. Epub 2005 Dec 20.
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.
拉索昔芬是一种选择性雌激素受体调节剂，可能会与其他药物联合使用，从而引发药物相互作用的问题。
采用一项为期7天的开放标签序贯研究，以确定稳态浓度的拉索昔芬是否会影响细胞色素P450介导的药物代谢。
在18名绝经后女性中使用拉索昔芬与CYP2E1和CYP2D6的探针药物进行试验。在不存在（第1天）和存在（第6天）拉索昔芬的情况下，通过给予250mg氯唑沙宗后6-羟基氯唑沙宗（6-OHCLZ；Cl(f,6-OHCLZ)）的生成清除率来测量CYP2E1代谢的变化。在不存在和存在拉索昔芬（第2天和第7天）的情况下，通过右美沙芬/右啡烷尿液代谢比值（MRDX）测量给予30mg右美沙芬后对CYP2D6代谢的影响。
稳态拉索昔芬不影响6-OHCLZ的生成清除率或尿液MRDX。对于6-OHCLZ，Cl(f,6-OHCLZ)比值（第6天/第1天）的90%置信区间的下限（87.12%）远高于临床可接受的60%的比值。在不存在和存在拉索昔芬的情况下，个体和组平均Cl(f,6-OHCLZ)值具有可比性。对于MRDX，MRDX比值（第7天/第2天）的90%置信区间的上限（129.37%）远低于规定的200%的比值。在不存在和存在拉索昔芬的情况下，个体和平均MRDX值具有可比性。拉索昔芬耐受性良好；不良事件轻微且短暂。
拉索昔芬对CYP2E1或CYP2D6介导的药物代谢没有影响，并且不应影响由其他细胞色素P450同工酶代谢的药物。
