Fate of quinidine, a P-glycoprotein substrate, in the gastrointestinal tract after oral administration in rats.
P-Glycoprotein (P-gp), an ATP-dependent efflux transporter, is expressed in brush-border membranes in the intestines of humans and rodents. In this study, the fate of quinidine, a P-gp substrate, in the gastrointestinal tract after oral administration was examined in conscious rats. The animals received quinidine (3 mg/ml/kg) or FITC-dextran of molecular weight of 10,000 (FD-10S, 5 mg/ml/kg, a poorly absorbable compound) orally, and the remaining amount of the compound in the upper gastrointestinal tract was measured at designated time intervals. As a control, FD-10S was distributed almost evenly throughout the gastrointestinal tract at 30 min, and most of FD-10S was accumulated in the distal small intestine at 60 min after administration. In contrast, most of the orally administered quinidine disappeared at the proximal intestine, and only small amounts reached the distal region. Also, the gastrointestinal transit of FD-10S was markedly slowed by stopping or inhibiting the bile flow, indicating that bile flow significantly affects the transit of drugs in the gastrointestinal tract. In conclusion, this study has demonstrated that compounds with high solubility and high permeability, such as quinidine, can be absorbed rapidly at the proximal intestine,escaping the barrier function of P-gp, because P-gp is mostly expressed in the distal intestine.
Mori
N
N
Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.
Yokooji
T
T
Murakami
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000502:physiology; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D007202:Indicators and Reagents; D008297:Male; D011802:Quinidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007202:Indicators and Reagents; D011802:Quinidine