Method to estimate the rate and extent of intestinal absorption in conscious rats using an absorption probe and portal blood sampling.
OBJECTIVE
A variety of methods exist which determine the rate and extent of intestinal absorption. The method described here employs an internal absorption reference probe and portal blood sampling in unanesthetized rat.


METHODS
Theophylline and tritiated water were selected as absorption reference probes since they are quantitatively absorbed in conscious rat. The fraction of an intestinal dose which reaches portal blood was determined from the resulting portal-systemic blood concentration gradients of the drug relative to the absorption probe. The absorption probes provide a means to calculate the drug mass reaching portal blood without the need of measuring the portal blood flow rate. The technique was evaluated with verapamil and a well-absorbed 5-lipoxygenase inhibitor, A-79035.


RESULTS
The fraction of an intrajejunal dose of A-79035 reaching the portal vein (FG) was 0.86 using theophylline as the absorption probe. Verapamil, which is susceptible to extensive hepatic first-pass elimination, was completely absorbed (FG = 0.98) within 1 hour, but was only 21.4% bioavailable. Absorption rate constants, estimated from initial appearance rates in portal blood, were used to monitor factors that affect drug absorption. For example, with a dose solution containing 30% PEG-400, the absorption rate constants of theophylline and A-79035 were significantly reduced. Anesthesia reduced the absorption rate constant for theophylline in rats by 40% compared to conscious animals.


CONCLUSIONS
The technique detailed here allows reliable, direct measurement of intestinal absorption which may assist in characterizing oral dosing for novel therapeutic agents.
Hoffman
D J
DJ
Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Seifert
T
T
Borre
A
A
Nellans
H N
HN
D000818:Animals; D001682:Biological Availability; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008433:Mathematics; D011169:Portal Vein / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000097:blood* / Q000493:pharmacokinetics*; D013997:Time Factors; D014700:Verapamil / Q000493:pharmacokinetics
D013806:Theophylline; D014700:Verapamil