Factors responsible for the variability of saquinavir absorption: studies using an instrumented dog model.
OBJECTIVE
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. (F(A): 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(-1) kg(-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.
Tam-Zaman
Nuzhat
N
Pharmacokinetics/Pharmacodynamics Department, Kinetana Group Inc., 108 Advanced Technology Center, Edmonton, Alberta, Canada. ntzaman@kinetana.com
Tam
Yun K
YK
Tawfik
Soheir
S
Wiltshire
Hugh
H
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D007408:Intestinal Absorption; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D019258:Saquinavir
D019258:Saquinavir