Effect of the interaction of drug-.BETA.-cyclodextrin complex with bile salts on the drug absorption from rat small intestinal lumen.

Nakanishi, Kunio; Masada, Mikio; Nadai, Tanekazu; Miyajima, Kouichiro

doi:10.1248/cpb.37.211

Cited by 50 publications

(19 citation statements)

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“…Indeed, cyclodextrins are well known for their ability to increase substantially the aqueous solubility, stability and bioavailability of lipophilic drugs, so that they are suitable carriers for anandamide [21]. In this respect, it should be noted that only the free drug, and not the cyclodextrin-drug complex can penetrate across the biological membranes [22]. In any case, we carefully controled that under our experimental conditions, 4.2 mM of MβCD alone has no effect on the capacitance and resistance of lipid bilayers (not shown).…”

Section: Resultsmentioning

confidence: 99%

The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent

et al. 2009

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BackgroundAnandamide is a lipid neurotransmitter which belongs to a class of molecules termed the endocannabinoids involved in multiple physiological functions. Anandamide is readily taken up into cells, but there is considerable controversy as to the nature of this transport process (passive diffusion through the lipid bilayer vs. involvement of putative proteic transporters). This issue is of major importance since anandamide transport through the plasma membrane is crucial for its biological activity and intracellular degradation. The aim of the present study was to evaluate the involvement of cholesterol in membrane uptake and transport of anandamide.Methodology/Principal FindingsMolecular modeling simulations suggested that anandamide can adopt a shape that is remarkably complementary to cholesterol. Physicochemical studies showed that in the nanomolar concentration range, anandamide strongly interacted with cholesterol monolayers at the air-water interface. The specificity of this interaction was assessed by: i) the lack of activity of structurally related unsaturated fatty acids (oleic acid and arachidonic acid at 50 nM) on cholesterol monolayers, and ii) the weak insertion of anandamide into phosphatidylcholine or sphingomyelin monolayers. In agreement with these data, the presence of cholesterol in reconstituted planar lipid bilayers triggered the stable insertion of anandamide detected as an increase in bilayer capacitance. Kinetics transport studies showed that pure phosphatidylcholine bilayers were weakly permeable to anandamide. The incorporation of cholesterol in phosphatidylcholine bilayers dose-dependently stimulated the translocation of anandamide.Conclusions/SignificanceOur results demonstrate that cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and bilayers, and its transport across bilayer membranes. In this respect, we suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery. Finally, this study provides a mechanistic explanation for the key regulatory activity played by membrane cholesterol in the responsiveness of cells to anandamide.

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Section: Resultsmentioning

confidence: 99%

The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent

et al. 2009

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“…Others have also observed the absorption of small amounts of cyclodextrin through the GI tract of rats when given alone 133,134 or as a complex with a drug. 135,136 Uekama et al 25 also briefly reviewed the absorption-enhancing effects of cyclodextrins given by various routes including oral administration. While it is correct to assume that the largest impact of cyclodextrins on oral drug absorption results from an increased rate of drug dissolution of the complexed drug, the magnitude of the stability constant between the drug and the cyclodextrin should also be considered since only the free, uncomplexed drug is absorbed through the GI mucosa.…”

Section: Oral Applications Of Cyclodextrinsmentioning

confidence: 99%

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

Rajewski¹,

Stella²

1996

Journal of Pharmaceutical Sciences

763

374

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The objective of this Review is to summarize and critique recent findings and applications of both unmodified and modified cyclodextrins for in vivo drug delivery. This review focuses on the use of cyclodextrins for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal, rectal, and pulmonary delivery are also briefly addressed. This Review primarily focuses on newer findings concerning cyclodextrin derivatives which are likely to receive regulatory acceptance due to improved aqueous solubility and safety profiles as compared to the unmodified cyclodextrins. Many of the applications reviewed involve the use of hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) and sulfobutylether-beta-cyclodextrins (SBE-beta-CDs) which show promise of greater safety while maintaining the ability to form inclusion complexes. The advantages and limitations of HP-beta-CD, SBE-beta-CD, and other cyclodextrins are addressed.

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“…In general, cyclodextrins are well-known for their ability to form inclusion complexes with hydrophobic drugs (15). Drug/p-CD inclusion complex and p-CD itself do not penetrate across biological membranes largely due to the hydrophilic character of CDs (27,28). Thus, drug/p-CD complexes must dissociate before drug absorption.…”

Section: Discussionmentioning

confidence: 99%

“…However, coadministration of !SBE4-p~CD at high concentrations reduced the miotic response of the pilocarpine prodrug solution. As discussed earlier, it is generally assumed that only free drug, not drug/cyclodextrin complex, can penetrate across biological membranes (27,28,38). Consequently, substantial complexation of pilocarpine prodrug with SBE4-p-CD can be expected to decrease the ocular delivery of pilocarpine prodrug due to a significant decrease in traction of free pilocarpine prodrug in solution.…”

Section: Discussionmentioning

confidence: 99%

Sulfobutyl Ether β-Cyclodextrin (SBE-β-CD) in Eyedrops Improves the Tolerability of a Topically Applied Pilocarpine Prodrug in Rabbits

Järvinen¹,

Järvinen²,

Urtti³

et al. 1995

Journal of Ocular Pharmacology and Therapeutics

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The effects of a novel, modified p-cyclodextrin (SBE4-p-CD; a variably substituted sulfobutyl ether with an average degree of substitution of four) on eye irritation and miotic response of an ophthalmically applied pilocarpine prodrug, 0,0'-dipropionyl-(l,4-xylylene) bispilocarpate, in albino rabbits were studied. Compared to the commercial pilocarpine eyedrop solution (163 mM, equivalent to 3.4% pilocarpine), 12-24 mM pilocarpine prodrug solutions (equivalent to 0.5 -1.0% pilocarpine, respectively) decreased peak miotic intensity (I max ) and increased the time to reach peak (t max ), but did not significantly affect values for the area under the miosis versus time curves (AUC), i.e. 12 -24 mM pilocarpine prodrug appeared to be equivalent to 163 mM pilocarpine. Ocularly applied 12-24 mM pilocarpine prodrug solutions, however, were more irritating than a commercial pilocarpine eyedrop solution. Coadministered SBE4-p-CD significantly decreased the eye irritation of the pilocarpine prodrug solutions. Coadministered SBE4-P-CD did not affect the miotic response of prodrug solution when the molar ratio of SBE4-p-CD to prodrug was low. However, increasing the molar ratio of SBE4-p-CD to prodrug decreased the I max and AUC values. The results show that eye irritation of the pilocarpine prodrug is prevented by levels of SBE4-P-CD that do not affect the apparent ocular absorption of the prodrug.

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Effect of the interaction of drug-.BETA.-cyclodextrin complex with bile salts on the drug absorption from rat small intestinal lumen.

Cited by 50 publications

References 0 publications

The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent

The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

Sulfobutyl Ether β-Cyclodextrin (SBE-β-CD) in Eyedrops Improves the Tolerability of a Topically Applied Pilocarpine Prodrug in Rabbits

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