Oral contraception does not alter single dose saquinavir pharmacokinetics in women
Oral contraception does not alter single dose saquinavir pharmacokinetics in women
复制标题
DOI：
10.1111/j.1365-2125.2003.01983.x
复制
发表时间：
2004-03-01
影响因子：
3.4
通讯作者：
Haefeli, WE
中科院分区：
文献类型：
--
作者：
Fröhlich, M;Burhenne, J;Haefeli, WE
目的女性在接受抗逆转录病毒治疗时的药物不良反应（ADR）多于男性。这可能是由于与激素制剂的药代动力学相互作用导致蛋白酶抑制剂的血浆浓度升高。因此，在本研究中，我们旨在研究口服避孕药（OC）对蛋白酶抑制剂沙奎那韦（saquinavir）药代动力学的影响。方法采用硬明胶胶囊制剂（Invirase(R)）给药，排除较常用的软明胶胶囊的药物辅助混淆。在一项前瞻性、固定顺序的研究设计中，8名健康女性受试者在第19次联合低剂量OC （0.03 mg炔雌醇，0.075 mg孕酮）之前和之后，分别服用单次口服剂量600 mg沙奎那韦。第一次沙奎那韦应用计划在个体月经周期的第1、2或3天。采用LC/MS/MS法测定沙奎那韦的血浆浓度及其m2和m3羟基代谢物的相对浓度48 h。结果服用OC后，与OC治疗第19天相比，服用OC前血清17 - β -雌二醇浓度显著降低-23.4 pg ml(-1) (57%, 95%CI: -76% ~ -37.4%)；孕酮-0.25 ng ml(-1) (33%, 95%CI: -45.3% ~ -21.5%)；促卵泡激素降低-4.06 μ l(-1) (82%, 95%CI: -96.5% ~ -67.7%)；黄体生成素降低-3.49 μ l(-1) （74%, 95%CI: -93 ~ -54.6%）。相反，性激素结合球蛋白的血清浓度增加了83.6 nmol l(-1) （205%, 95%CI: 32.2% ~ 377%）。沙奎那韦的药代动力学参数（AUC、C-max、t（max）、t（1/2）、CLR）不受OC的影响，沙奎那韦/ m2和m3 -羟基沙奎那韦的相对代谢比也不受OC的影响。此外，血清激素浓度或mdr1多态性（C3435T和G2677T）与沙奎那韦的药代动力学参数没有关联。结论OC对沙奎那韦的药动学无影响。因此，合成性类固醇与沙奎那韦的药代动力学相互作用不太可能解释女性抗逆转录病毒治疗不良反应增加的原因。
AimsWomen experience more adverse drug reactions (ADR) to antiretroviral therapy than men. This may be attributed to higher plasma concentrations of protease inhibitors due to pharmacokinetic interactions with hormonal preparations. Thus, in the present study we aimed to investigate the influence of oral contraceptives (OC) on the pharmacokinetics of the protease inhibitor saquinavir.MethodsSaquinavir was administered in a hard gelatin capsule formulation (Invirase(R)) to rule out confounding by pharmaceutical aids of the more frequently used soft gelatin capsule. After an overnight fast, eight healthy female participants ingested a single oral dose of 600 mg saquinavir immediately before and after the 19th dose of a combined, low dose OC (0.03 mg ethinylestradiol, 0.075 mg gestodene) in a prospective, fixed sequence study design. The first saquinavir application was scheduled on day 1, 2, or 3 of the individual menstrual cycle. Plasma concentrations of saquinavir and relative concentrations of its M2&M3-hydroxy metabolites were determined by LC/MS/MS for 48 h.ResultsIntake of OC resulted in a significant decrease in morning serum concentrations (before intake of OC, compared to day 19 of OC therapy) of 17beta-estradiol by -23.4 pg ml(-1) (57%, 95%CI: -76% to -37.4%); progesterone by -0.25 ng ml(-1) (33%, 95%CI: -45.3% to -21.5%); follicle-stimulating hormone by -4.06 U l(-1) (82%, 95%CI: -96.5% to -67.7%); and luteinizing hormone by -3.49 U l(-1) (74%, 95%CI: -93 to -54.6%). Conversely, sexual hormone binding globulin serum concentrations increased by 83.6 nmol l(-1) (205%, 95%CI: 32.2% to 377%). Pharmacokinetic parameters of saquinavir (AUC, C-max, t(max), t(1/2), CLR) were not affected by OC, nor was the relative metabolic ratio of saquinavir/M2&M3-hydroxy saquinavir. Furthermore, there was no association of serum hormone concentrations or MDR1-polymorphisms (C3435T and G2677T) with pharmacokinetic parameters of saquinavir.ConclusionsThere was no effect of OC on saquinavir pharmacokinetics. Thus, pharmacokinetic interactions of synthetic sexual steroids with saquinavir are not likely to account for the increased ADR to antiretroviral therapy seen in women.