Evaluation of (+)-cyclaradine-5'-esters as prodrugs for (+)-cyclaradine in animals.

Both (+)-cyclaradine-5'-methoxyacetate (CM) and (+)-cyclaradine-5'-ethoxypropionate (CE) were converted to (+)-cyclaradine (C) in squirrel monkey and human sera at 37 degrees C. CE was more stable than CM. After oral administration (20 mg base equivalent per kg) of either CM or CE, no unchanged esters were observed in serum of squirrel monkeys, rabbits, or rats. Instead, C was detected, indicating conversions of CM and CE to C in vivo. In squirrel monkeys, the areas under the curve (AUCs) of C obtained from oral dosing with CM were 61% higher than those obtained from dosing with C, indicating that CM may be a good prodrug for C. In squirrel monkeys, rabbits, and rats, CE resulted in a 20 to 90% higher AUC of C than did CM, indicating that CE was better absorbed than CM.