Improvement of intestinal absorption of P-glycoprotein substrate by D-tartaric acid.
The purpose of the present experiment was to examine the effects of D-tartaric acid (TA) on intestinal drug absorption under both in situ and in vitro experimental conditions. In the in vitro diffusion chamber experiments, TA (10 mM) added to the mucosal side of rat colon significantly decreased rhodamine123 (Rho 123) transport from the serosal to mucosal side. Since TA has been shown to change the integrity of the epithelial tight junctions in rat colon at low pH conditions, resulting in improved paracellular drug transport, the effect of TA on membrane resistance was examined at pH 7.4 in the present study. It was found that membrane resistance, an indicator of paracellular integrity, did not change at pH 7.4. In the in situ loop method, TA (20 mM) increased the absorption of Rho123 in both ileum and colon but not in jejunum. TA (20 mM) also increased the absorption of daunorubicin in the ileum, but TA (20 mM) did not change the expression level of P-glycoprotein (P-gp). TA (20 mM) significantly inhibited excretion of i.v.-administered Rho123 and daunorubicin into the ileal lumen. In conclusion, for the first time we demonstrated that TA increases the intestinal absorption of P-gp substrates Rho123 and daunorubicin, possibly by modulating the P-gp function without changing the expression level of P-gp in the rat intestine.
Iida
Aiko
A
Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan. aiai_dada@hotmail.com
Tomita
Mikio
M
Idota
Yoko
Y
Takizawa
Yusuke
Y
Hayashi
Masahiro
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D015194:Diffusion Chambers, Culture / Q000379:methods; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D007082:Ileum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D007583:Jejunum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics*; D013644:Tartrates / Q000494:pharmacology*; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D005456:Fluorescent Dyes; D013644:Tartrates; D020112:Rhodamine 123; D014700:Verapamil; C029768:tartaric acid; D003630:Daunorubicin