PHARMACOKINETICS OF GESTODENE AND ETHINYLESTRADIOL IN 14 WOMEN DURING3 MONTHS OF TREATMENT WITH A NEW TRI-STEP COMBINATION ORAL-CONTRACEPTIVE - SERUM-PROTEIN BINDING OF GESTODENE AND INFLUENCE OF TREATMENT ONFREE AND TOTAL TESTOSTERONE LEVELS IN THE SERUM

The pharmacokinetics of gestodene (GEST) and ethinylestradiol EE(2) we re determined in 14 healthy women (age 18 to 32 years) during a treatm ent period of three months with a new tri-step combination oral contra ceptive (Milvane(R)). Prior to this treatment period, the same women r eceived a single administration of a coated tablet containing 0.1 mg G EST together with 0.03 mg EE(2). There was a wash-out phase of one wee k between both treatments. Following single dose administration, a mea n terminal half-life of 18 h was observed for GEST. The total clearanc e was 0.9 ml x min(-1) x kg(-1) and the volume of distribution was 84 1. During a treatment cycle, GEST levels in the serum accumulated by a factor of 8 as compared to single dose administration. Steady-state d rug levels were reached during the second half of each cycle. As compa red to single dose administration, the following changes were observed for GEST at the end of treatment cycles one and three: prolonged term inal 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 1). A concomitant EE(2)-induced increase in the S HBG concentrations by a factor of three as compared to pretreatment va lues was observed during a treatment cycle and appeared to be mainly r esponsible for the changes in the pharmacokinetics of GEST. Marked cha nges were also seen for the serum protein binding of GEST. After singl e dose administration, the free fraction of GEST was 1.3% and the frac tions 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 fractio ns 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) value s of EE(2) were 299.2 and 278.1 pg x ml(-1) x h, respectively, which c orresponds to an about 30% increase as compared to single dose adminis tration, 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 wit h the corresponding values measured prior to treatment. The fraction o f unbound testoster one thus decreased from 0.5 % to 0.3 % during trea tment.