PhD student/resident Mississippi state university starkville, Mississippi, United States
Abstract:
Background: Cyclosporine concentrations and pharmacodynamic effects in the canine liver and intestinal tract have not been evaluated. Hypothesis/
Objectives: Our objective was to determine drug concentration and pharmacodynamic effects in the blood, plasma, liver, and small intestine in dogs receiving oral cyclosporine. Our hypothesis was that the drug would concentrate in liver and intestine, with associated enhanced T-cell suppression in these locations. Animals: Six healthy Walker hounds.
Methods: Dogs were administered oral cyclosporine 2.5 mg/kg twice daily for 7 days. Before treatment and again 2 hours after the final dose, blood samples, laparoscopic liver biopsies, and endoscopic small intestinal biopsies were collected under general anesthesia. Liquid chromatography-mass spectrometry was used to measure cyclosporine concentrations. Activated T-cell interleukin-2 (IL-2) expression was measured by quantitative reverse transcription PCR. Percentage immune suppression (IS) was calculated by differences in PCR cycle threshold after administration of cyclosporine.
Results: Cyclosporine concentrations in liver (2537 ± 1232 ng/ml) and intestine (5323 ± 6697 ng/ml) were markedly higher (P< 0.01) than in blood (373 ± 200 ng/ml) and plasma (138 ± 98 ng/ml). In contrast, T-cell IL-2 expression was significantly more suppressed in blood (IS 51 ± 17%) than in liver (IS 16 ± 28%) or intestine (IS 2 ± 39%) (P< 0.01). No correlation was found between cyclosporine concentration and IS between tissues (P=0.724). Conclusions and Clinical Importance: Surprisingly, pharmacodynamic effects in intestine and liver do not correlate with high cyclosporine concentrations. Further studies are needed to determine why high tissue concentrations do not lead to enhanced local T-cell suppression.
