Vascular perfused segments of human intestine as a tool for drug absorption.
Blood-based vascular perfusion of isolated segments of human jejunum was developed as a tool for drug absorption studies before clinical trials. Acceptance criteria for viable human gut preparations included stable blood flow, arterial pressure, glucose utilization, active peristalsis, oxygen uptake, less than 3% absorption of a 70,000 mol. wt. dextran, and a ratio of first-order absorption rate constants (k(a)) of antipyrine to terbutaline of > or =1.4. Mannitol absorption was less than that of antipyrine but larger than that of terbutaline and could not be used as a negative control in absorption studies with human intestine. In separate perfusions (n = 3) a cassette of nine drugs was administered into the gut lumen, and the net absorption of each drug into the circulation was measured over 75 min. Using the mean values of k(a), the test compounds could be ranked into four groups: group 1: sulfasalazine and furosemide, k(a) = 3.9 to 4.0 x 10(-3) min(-1); group 2: cimetidine, timolol, nadolol, and ranitidine, k(a) = 6.4 to 8.3 x 10(-3) min(-1); group 3: atenolol and metoprolol, k(a) = 9.6 x 10(-3) min(-1); and group 4: theophylline, k(a) = 17.5 x 10(-3) min(-1). The rationale for evaluating yet another oral absorption system was as follows: first, a human gut segment with an intact vascular system is the closest system available to a clinical trial without performing one; and second, the data generated would be a direct measure of net drug transport from the gut lumen into the vascular circulation under near physiological conditions, which is not possible in models lacking a blood supply.
Wei
Yansheng
Y
Bowman Research Inc., Des Plaines, IL 60018, USA.
Neves
Liomar A A
LA
Franklin
Tammy
T
Klyuchnikova
Nadya
N
Placzek
Benjamin
B
Hughes
Helen M
HM
Curtis
C Gerald
CG
D000328:Adult; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007422:Intestines / Q000098:blood supply*; D008297:Male; D010599:Pharmacokinetics; D055815:Young Adult