The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR-RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4 mgkg(-1)). The plasma concentrations of cyclosporine were measured for up to 24 h post dose by high-performance liquid chromatography-electrospray mass spectrometry. We found that the mean Cmax (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng ml(-1) (*18B/*18B)(p = 0.037) and the mean AUCO-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml(-1) h (*18B/*18B) (p=0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, Tmax exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2 h post dose compared with *1/*18B (p = 0.062) or *1/*1 (p = 0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p > 0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.

Climate change can affect the habitat resources available to species by changing habitat quantity, suitability and spatial configuration, which largely determine population persistence in the landscape. In this context, dispersal is a central process for species to track their niche. Assessments of the amount of reachable habitat (ARH) using static snap‐shots do not account, however, for the temporal overlap of habitat patches that may enhance stepping‐stone effects. Here, we quantified the impacts of climate change on the ARH using a spatio–temporal connectivity model. We first explored the importance of spatio–temporal connectivity relative to purely spatial connectivity in a changing climate by generating virtual species distributions and analyzed the relative effects of changes in habitat quantity, suitability and configuration. Then, we studied the importance of spatio–temporal connectivity in three vertebrate species with divergent responses to climate change in North America (grey wolf, Canadian lynx and white‐tailed deer). We found that the spatio–temporal connectivity could enhance the stepping‐stone effect for species predicted to experience range contractions, and the relative importance of the spatio–temporal connectivity increased with the reduction in habitat quantity and suitability. Conversely, for species that are likely to expand their ranges, spatio–temporal connectivity had no additional contribution to improve the ARH. We also found that changes in habitat amount (quantity and suitability) were more influential than changes in habitat configuration in determining the relative importance of spatio–temporal connectivity. We conclude that spatio–temporal connectivity may provide less biased and more realistic estimates of habitat connectivity than purely spatial connectivity.

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