Pharmacokinetics of gestagens: some problems.

Various approaches to studying the pharmacokinetics of gestagens and the factors that influence derivation of the parameters are described with levonorgestrel used as an example. Published studies of the pharmacokinetics of levonorgestrel are reviewed, and new information is presented regarding intra- and intersubject variation. Differences between various formulations of levonorgestrel are apparent when the formulations are compared in the same subjects. There is also a marked difference in the parameters when derived under single-dose or steady-state conditions. The role of sex hormone-binding globulin in the metabolism of levonorgestrel is questioned. Large intra- and inter-subject variations in the parameters exist, and a subject may show a large month-to-month variation when one levonorgestrel formulation is used and smaller variations when another formulation is used. This wide variability in the pharmacokinetic parameters, problems that arise in the derivation and interpretation of the parameters, the biologic significance of most of these parameters, and their lack of correlation with pharmacodynamic responses severely limit the usefulness of pharmacokinetic studies of the gestagens.