Factors Responsible for the Variability of Saquinavir Absorption: Studies Using an Instrumented Dog Model
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Purpose. To study the effect of dose and food on the bioavailability of saquinavir in dogs.
Methods. A Youden Square block design was used for six female mongrel dogs (20-24 kg) who received six saquinavir treatments. The six randomized treatments were 1 mg/kg intravenous infusion over 30 min; 200, 400, 600, and 800 mg of saquinavir in the form of 200-mg capsules given orally with food; and 400 mg of saquinavir given orally after an overnight fast. A 200-mg 14C-saquinavir capsule was used to replace one of the 200-mg unlabeled saquinavir capsules in the 200- and 800-mg oral study.
Results. Absorption of saquinavir from the gut was variable. (FA: 49-95%). The 14C-saquinavir study shows that the total radioactivity absorbed from the gut was insignificantly different from that of unlabeled saquinavir, suggesting first-pass gut metabolism was unimportant. The bioavailability of saquinavir under fasting condition was significantly lower (8.41 ± 4.7% vs. 20.3 ± 2.6%, p < 0.05). Saquinavir underwent significant first-pass liver metabolism because hepatic clearance values (22 to 30 ml min-1kg-1) approached that of liver blood flow.
Conclusions. Incomplete gut absorption and extensive first-pass liver metabolism are the causes for low bioavailability of saquinavir in dogs. Absorption was further reduced under fasted conditions.
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