INTRASUBJECT VARIABILITY IN THE PHARMACOKINETICS OF ETHYNYLOESTRADIOL

Intrasubject and intersubject variability in the metabolism of ethynyloestradiol (EE) was assessed in a cross-over randomized study of 6 women who each received 3 months treatment with 50-mu-g EE and 50-mu-g EE with 250-mu-g levonorgestrel (LNG). Blood samples were collected at the end of each treatment month, assayed for EE and the half-life of elimination (T(el)) and bioavailability (area under the serum concentration-time curve, AUC) calculated. Intrasubject variability for T(el) and AUC varied markedly; the variability was random and not correlated with the formulation administered. The intrasubject variability for T(el) and AUC was 31 and 17%, respectively, and intersubject variability 66 and 95%. The intersubject range of values was more than 3-fold for both T(el) and AUC and the intrasubject range about 2-fold. The pharmacokinetics of EE were not influenced by LNG; mean values for T(el) and AUC were 17.3 +/- 5.5 h and 11.1 +/- 3.8 ng/ml/h, respectively, when EE was administered alone compared with 16.4 +/- 4.8 h and 12.5 +/- 3.9 ng/ml/h when given with LNG. However, EE influenced the metabolism of LNG; T(el) for LNG was 19.3 +/- 4.2 h when administered alone and significantly higher (30.0 +/- 11.2 h) when given with EE. There was no correlation between the rate of metabolism of EE and that of LNG. The intrasubject variability shown in this and other studies suggests that genetic factors are less important in intersubject variability than previously thought. Some implications of intrasubject variability are discussed.