Effect of cimetidine on pharmacokinetics of orally administered cyclosporine in healthy dogs

Objective-To describe the pharmacokinetics of cyclosporine (CyA) in healthy dogs after oral administration alone or in combination with orally adminis tered cimetidine. Animals-10 healthy adult Beagles. Procedure-Dogs were randomly assigned to receive CyA alone or CyA in combin ation with cimetidine. After a washout period of 2 weeks, dogs then receive d the alternate treatment. The CyA plus cimetidine treatment required admin istration of cimetidine (15 mg/kg of body weight, PO, q 8 h) for 8 days and administration of CyA (5 mg/kg, PO, q 24 h) on days 6 through 8. The CyA t reatment alone required administration of CyA (5 mg/kg, PO, q 24 h) for 3 d ays. On the third day of CyA administration during each treatment, blood sa mples were collected immediately before (time 0) and 0.5, 1, 1.5, 2, 2.5, 3 , 5, 7, 9, 11, 13, 15, 21, and 24 hours after initiating CyA administration . Results-Time until maximum CyA concentration was significantly longer for C yA in combination with cimetidine. Assessment of estimated pharmacokinetic variables revealed a significantly faster rate of change in the distributio n phase for CyA in combination with cimetidine. Maximum CyA concentration d iffered significantly among dogs but did not differ significantly between t reatments. Conclusions and Clinical Relevance-Analysis of our data suggests that cimet idine may affect absorption of orally administered CyA, but overall, it doe s not affect the pharmacokinetics of CyA. There is considerable variability in the maximum concentration of CyA among dogs, and monitoring of blood co ncentrations of CyA during treatment is advised.