Morphometric studies of the microvilli of the small intestine of rats in the presence of cyclosporine and its formulation excipients: Pharmacokinetic and pharmacodynamic condsiderations

Cyclosporine and its two marketed formulations were selected as model drug and formulations because cyclosporine has been repeatedly reported in the literature to have low and variable absorption (2--60%) and pharmacokinetics. In addition, cyclosporine is a low water soluble drug. We hypothesized that formulation factors, excipients and drugs can have an acute and also a long-term effect on the surface area of the small intestine.;In order to test our research hypothesis, morphometric studies of the microvilli of the duodenum, jejunum and ileum of male Sprague-Dawley rats were conducted to study acute changes of these anatomical regions after single oral administration of cyclosporine products and its formulation vehicles. In addition, multiple oral administration studies were also conducted for 28 days in order to illustrate the long-term effects on the surface area and height of the microvilli obtained from these anatomical regions. The results suggested that both Neoral(TM) vehicle and SandimmuneRTM vehicle (olive oil) increased the microvillous height. The observed increase was more pronounced after administration of Neoral(TM) vehicle (p < 0.05). In contrast, cyclosporine was observed to decrease the microvillous height but to a lesser extent when compared to the effects of the formulation vehicles (p < 0.05). Surprisingly, a reversal of the effects on the microvillous height was observed after multiple oral administrations of cyclosporine and its formulation vehicles for 28 days. The results of this dissertation may help clarify the variable absorption kinetics of cyclosporine that has been reported in the literature. In addition, the greater impact of the Neoral(TM) formulation on the apical microvillous height offers an alternative explanation for the improved and more consistent absorption of cyclosporine. Furthermore, it may also help explain the lack of change of the ratio of systemic concentrations of the major metabolites of cyclosporine to the parent compound. Finally, the baseline data obtained from the measurements of the height and the surface area of the microvilli of the anatomical regions of the small intestine of rats will set a foundation for further studies of other drugs and their formulations. (Abstract shortened by UMI.).