Study on absorption sites of quinidine and methotrexate in rat intestine.
Influx or efflux transporter(s), or both, are frequently involved in the intestinal absorption of various therapeutic drugs. In the present study, the effects of altered gastric emptying rates (GER) on intestinal absorption of quinidine (a substrate for P-glycoprotein, P-gp) and methotrexate (a substrate for multiple-transporters including proton-coupled folate transporter, PCFT) were examined to find their main absorption sites along the intestine employing rats. In untreated control rats, quinidine administered orally was rapidly absorbed from the proximal intestine, where P-gp is less expressed. Increased GER, which transferred an unabsorbable model compound to the middle intestine within 15 min after oral administration, exerted no significant effects on the extent of oral bioavailability of quinidine, whereas it increased the initial absorption rate greatly. Decreased GER, in which more than 50% of a model compound administered was retained in the stomach even 1 h after administration, decreased the onset time of intestinal absorption, but not the extent of oral bioavailability of quinidine. In untreated control rats, methotrexate was absorbed efficiently from the proximal intestine under acidic conditions, where PCFT is abundantly expressed. Increased GER significantly decreased, and decreased GER slightly increased the oral bioavailability of methotrexate. In conclusion, altered GER was found to affect the transporter-mediated intestinal absorption of drugs in different manners, depending on the solubility, membrane permeability, luminal concentration of the drug, luminal pH, substrate specificity, and the expression sites of transporter.
Murakami
T
T
Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Japan. t-muraka@ps.hirokoku-u.ac.jp
Yokooji
T
T
Mori
N
N
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002352:Carrier Proteins / Q000378:metabolism; D003911:Dextrans; D004386:Duodenum / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005746:Gastric Emptying / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008970:Molecular Weight; D011802:Quinidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000962:Antimalarials; D002352:Carrier Proteins; D003911:Dextrans; D005493:Folic Acid Antagonists; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate; D011802:Quinidine; D008727:Methotrexate