14名女性在使用一种新型三步联合口服避孕药治疗三个月期间炔诺孕酮和炔雌醇的药代动力学：炔诺孕酮的血清蛋白结合以及治疗对血清中游离睾酮和总睾酮水平的影响

Pharmacokinetics of gestodene and ethinylestradiol in 14 women during three months of treatment with a new tri-step combination oral contraceptive: serum protein binding of gestodene and influence of treatment on free and total testosterone levels in the serum.

作者信息

Kuhnz W, Baumann A, Staks T, Dibbelt L, Knuppen R, Jütting G

机构信息

Institut für Pharmakokinetik, Schering Aktiengesellschaft, Berlin, FRG.

出版信息

Contraception. 1993 Oct;48(4):303-22. doi: 10.1016/0010-7824(93)90077-k.

DOI:10.1016/0010-7824(93)90077-k

PMID:8222659

Abstract

The pharmacokinetics of gestodene (GEST) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 32 years) during a treatment period of three months with a new tri-step combination oral contraceptive (Milvane). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.1 mg GEST together with 0.03 mg EE2. There was a wash-out phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 18 h was observed for GEST. The total clearance was 0.9 ml x min-1 x kg-1 and the volume of distribution was 84 l. During a treatment cycle, GEST levels in the serum accumulated by a factor of 8 as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for GEST at the end of treatment cycles one and three: prolonged terminal half-life (20 to 22 h), reduced total (0.16 ml x min-1 x kg-1) and free clearance (ca. 27 ml x min-1 x kg-1), reduced volume of distribution (ca. 18 l). A concomitant EE2-induced increase in the SHBG concentrations by a factor of three as compared to pretreatment values was observed during a treatment cycle and appeared to be mainly responsible for the changes in the pharmacokinetics of GEST. Marked changes were also seen for the serum protein binding of GEST. After single dose administration, the free fraction of GEST was 1.3% and the fractions bound to SHBG and albumin were 69.4% and 29.3%, respectively. At the end of cycle one, the free fraction was only 0.6% and the fractions bound to SHBG and albumin were 81.4% and 18.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of GEST at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 299.2 and 278.1 pg x ml-1 x h, respectively, which corresponds to an about 30% increase as compared to single dose administration, where an AUC(0-4h) value of 216.1 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 36% and 60%, respectively, compared with the corresponding values measured prior to treatment. The fraction of unbound testosterone thus decreased from 0.5% to 0.3% during treatment.

摘要

在14名健康女性（年龄18至32岁）使用新型三步联合口服避孕药（米瓦内）进行为期三个月的治疗期间，测定了孕二烯酮（GEST）和炔雌醇（EE2）的药代动力学。在该治疗期之前，这些女性接受了一次含有0.1 mg GEST和0.03 mg EE2的包衣片给药。两次治疗之间有一周的洗脱期。单剂量给药后，观察到GEST的平均终末半衰期为18小时。总清除率为0.9 ml·min⁻¹·kg⁻¹，分布容积为84升。在一个治疗周期中，血清中GEST水平与单剂量给药相比累积了8倍。在每个周期的后半期达到稳态药物水平。与单剂量给药相比，在治疗周期一和三结束时观察到GEST有以下变化：终末半衰期延长（20至22小时），总清除率降低（0.16 ml·min⁻¹·kg⁻¹）和游离清除率降低（约27 ml·min⁻¹·kg⁻¹），分布容积降低（约18升）。在一个治疗周期中观察到，与治疗前值相比，EE2引起的性激素结合球蛋白（SHBG）浓度增加了三倍，这似乎是导致GEST药代动力学变化的主要原因。GEST的血清蛋白结合也有明显变化。单剂量给药后，GEST的游离分数为1.3%，与SHBG和白蛋白结合的分数分别为69.4%和29.3%。在周期一结束时，游离分数仅为0.6%，与SHBG和白蛋白结合的分数分别为81.4%和18.0%。在周期一和三结束时，GEST的相应药代动力学参数和血清蛋白结合没有差异。在治疗周期一和三的最后一天，EE2的AUC(0 - 4h)值分别为299.2和278.1 pg·ml⁻¹·h，与单剂量给药（AUC(0 - 4h)值为216.1 pg·ml⁻¹·h）相比增加了约30%。与治疗前测量的相应值相比，在治疗周期一和三期间，总睾酮和游离睾酮浓度分别下降了约36%和60%。因此，治疗期间未结合睾酮的分数从0.5%降至0.3%。