PHARMACOKINETICS OF TIQUESIDE (BETA-TIGOGENIN CELLOBIOSIDE) IN DOGS, RATS, RABBITS, AND MONKEYS

Tiqueside (CP-88,818, beta-tigogenin cellobioside) is an effective cho lesterol absorption inhibitor that may be useful in the treatment of h ypercholesteremia. We have investigated the pharmacokinetics of tiques ide in dogs, rats, rabbits, and monkeys. In dogs, the volume of distri bution (Vd(ss)) was 2.11 L/kg, clearance was 0.58 mL/min.kg, and half- life was 45 h following a 1.4 mg/kg intravenous dose. Absolute bioavai lability in fed dogs decreased from 6.7% for a 30 mg/kg dose to 1.7% f or a 375 mg/kg dose. The oral bioavailability at a dose of 375 mg/kg w as approximately 4-fold lower in fasted dogs than fed dogs. AUC-(0-24) for doses up to 2000 mg/kg were only slightly greater than AUC-(0-24) for a 375 mg/kg dose. In rats dosed intravenously at 8.0 mg/kg, Vd(ss ) was 3.52 L/kg, clearance was 14.6 mL/min.kg, and half-life was 3.6 h . Estimated bioavailability for rats dosed in feed at 250-2000 mg/kg/d ay was less than 0.5%. In rabbits dosed at 4.0 mg/kg iv, Vd(ss) was 2. 95 L/kg, clearance was 0.59 mL/min.kg, and half-life was 61 h. Bioavai lability for rabbits dosed in feed at 62.5 or 125 mg/kg/day was approx imately 7%. Systemic exposure in rhesus monkeys after oral dosing was lower than that for dogs and rabbits. Thus, low systemic exposure to t iqueside following oral administration has been demonstrated in severa l animal species.