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Mechanistic analysis for drug permeation through intestinal membrane.
Drug Metab Pharmacokinet. 2007 Apr; 22(2):67-77.DM

Abstract

For drug absorption, intestinal drug permeability's through both the paracellular and transcellular routes were analyzed. Absorption enhancers, such as sodium caprate (C10), decanoylcarnitine (DC) and tartaric acid (TA), increased the paracellular permeability of water-soluble, low lipophilic and poorly absorbable drugs by enlargement of tight junction (TJ) adhering to the intercellular portion; that is, expansion of the paracellular routes. C10 increased the intracellular calcium level to induce contraction of calmodulin-dependent actin filaments. Although DC also increased the intracellular calcium level, the action was independent of calmodulin, and thus the action mechanism of DC was considered to differ from that of C10. DC and TA decreased the intracellular ATP level and the intracellular pH, suggesting that intracellular acidosis increases the calcium level through decrease in ATP level followed by opening TJ. TA had no effect on Western blot analysis, but TA significantly inhibited excretion of rhodamine 123, one of the P-glycoprotein (P-gp) substrates, from the serosal to mucosal side, suggesting that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp. During ischemia/reperfusion (I/R) injury during small intestine grafting, TJ opening and decrease in P-gp function simultaneously occurred. The in vitro model of I/R showed that lipid peroxidation is a trigger of the injury, and superoxide and iron ion participate in TJ opening and decrease in P-gp function. Colonic epithelial cells have the specific transcellular transport systems for lipopolysaccharide (LPS), one of which shows substrate specificity in the interaction with CD14 and/or that of TLR4. In the infective disease induced by LPS, the mucosal LPS sensitive transport capability was decreased and in the secretory direction, the receptor-mediated uptake mechanism disappeared. LPS taken up into the cells can be excreted by P-gp or mrp. The expression levels and function of the secretory transporters were considered to be increased in the infective condition. In conclusion, changes in TJ as the membrane structure and P-gp as the membrane function are important factors controlling intestinal membrane transport.

Authors+Show Affiliations

Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Japan. hayashi@ps.toyaku.ac.jpNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

17495413

Citation

Hayashi, Masahiro, and Mikio Tomita. "Mechanistic Analysis for Drug Permeation Through Intestinal Membrane." Drug Metabolism and Pharmacokinetics, vol. 22, no. 2, 2007, pp. 67-77.
Hayashi M, Tomita M. Mechanistic analysis for drug permeation through intestinal membrane. Drug Metab Pharmacokinet. 2007;22(2):67-77.
Hayashi, M., & Tomita, M. (2007). Mechanistic analysis for drug permeation through intestinal membrane. Drug Metabolism and Pharmacokinetics, 22(2), 67-77.
Hayashi M, Tomita M. Mechanistic Analysis for Drug Permeation Through Intestinal Membrane. Drug Metab Pharmacokinet. 2007;22(2):67-77. PubMed PMID: 17495413.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanistic analysis for drug permeation through intestinal membrane. AU - Hayashi,Masahiro, AU - Tomita,Mikio, PY - 2007/5/15/pubmed PY - 2007/6/8/medline PY - 2007/5/15/entrez SP - 67 EP - 77 JF - Drug metabolism and pharmacokinetics JO - Drug Metab Pharmacokinet VL - 22 IS - 2 N2 - For drug absorption, intestinal drug permeability's through both the paracellular and transcellular routes were analyzed. Absorption enhancers, such as sodium caprate (C10), decanoylcarnitine (DC) and tartaric acid (TA), increased the paracellular permeability of water-soluble, low lipophilic and poorly absorbable drugs by enlargement of tight junction (TJ) adhering to the intercellular portion; that is, expansion of the paracellular routes. C10 increased the intracellular calcium level to induce contraction of calmodulin-dependent actin filaments. Although DC also increased the intracellular calcium level, the action was independent of calmodulin, and thus the action mechanism of DC was considered to differ from that of C10. DC and TA decreased the intracellular ATP level and the intracellular pH, suggesting that intracellular acidosis increases the calcium level through decrease in ATP level followed by opening TJ. TA had no effect on Western blot analysis, but TA significantly inhibited excretion of rhodamine 123, one of the P-glycoprotein (P-gp) substrates, from the serosal to mucosal side, suggesting that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp. During ischemia/reperfusion (I/R) injury during small intestine grafting, TJ opening and decrease in P-gp function simultaneously occurred. The in vitro model of I/R showed that lipid peroxidation is a trigger of the injury, and superoxide and iron ion participate in TJ opening and decrease in P-gp function. Colonic epithelial cells have the specific transcellular transport systems for lipopolysaccharide (LPS), one of which shows substrate specificity in the interaction with CD14 and/or that of TLR4. In the infective disease induced by LPS, the mucosal LPS sensitive transport capability was decreased and in the secretory direction, the receptor-mediated uptake mechanism disappeared. LPS taken up into the cells can be excreted by P-gp or mrp. The expression levels and function of the secretory transporters were considered to be increased in the infective condition. In conclusion, changes in TJ as the membrane structure and P-gp as the membrane function are important factors controlling intestinal membrane transport. SN - 1347-4367 UR - https://www.unboundmedicine.com/medline/citation/17495413/Mechanistic_analysis_for_drug_permeation_through_intestinal_membrane_ L2 - http://joi.jlc.jst.go.jp/JST.JSTAGE/dmpk/22.67?from=PubMed DB - PRIME DP - Unbound Medicine ER -