Retinoid Absorption from Simple and Mixed Micelles in the Rat Intestine

doi:10.1002/jps.2600841118

Journal of Pharmaceutical Sciences

Volume 84, Issue 11, November 1995, Pages 1360-1365

https://doi.org/10.1002/jps.2600841118 Get rights and content

Abstract

▭ The absorption of three retinoid analogs etretinate (ET), acitretin (ETA), and motretinid (MOE) from two distinct micellar systems was studied in the rat intestine. Each of the three drugs was loaded into simple micelles consisting of 10 mM sodium taurocholate (NaTC) and mixed micelles consisting of 10 mM egg phosphatidylcholine (PC) and 10 mM NaTC. Following perfusion through the jejunum segments, both the fraction of drug disappearing from the segment and the permeability of the drug from the lumen into the gut wall (P_eff) was greater with the mixed micelles as compared to the simple micelles. Perfusion flow rate had an influence on the P_eff for ET and ETA. Similar trends as for the jejunum were seen in the ileum perfusions. The simultaneous uptake of PC and NaTC during the retinoid perfusions was monitored. There appeared to be a correlation between the P_eff values for PC and that of the retinoids. The viability of the in-situ perfusion system was confirmed histologically. There is evidence to indicate that the permeability of the intestine is sensitive to subtle differences in the chemical structure of the retinoids.

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The mixed micelles formed by bile salts and lecithin have been widely used as carriers for insoluble oral drugs. The increase in the bioavailability of drugs by mixed micelles may be caused mainly by the increased solubility and permeability across gastrointestinal epithelia (Pithavala et al., 1995). However, detailed studies on the effects of mixed micelles on the gastrointestinal epithelia have been lacking to reveal their potential toxicity.
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Gentamicin (GM) is an important aminoglycoside antibiotic for the treatment of infections caused by a wide spectrum of aerobic gram-negative bacilli and gram-positive cocci. As a class, the aminoglycosides are poorly absorbed from the gastrointestinal (GI) tract and are commonly used as injectable and topical preparations. This study was aimed at finding the effect of a novel emulsifier, Labrasol, on the absorption of GM from the GI tract of rats. GM formulations were prepared, either as saline solution or as Labrasol microemulsions, and were administrated to rat small intestine and colon. Plasma GM levels following intestinal application were compared to those obtained with intravenous (i.v.) administration. A 5 mg/kg dose of GM preparation containing Labrasol, 1 ml/kg, administrated into colon resulted in the mean AUC of 21.179±1.374 μg×h/ml, compared to 7.813±0.105 μg×h /ml obtained with i.v. administration of GM, 1 mg/kg. The absolute bioavailability (BA) of the Labrasol preparation was 54.2 %. Labrasol facilitates the transmucosal delivery of GM from rat colon by forming microemulsions, and the BA obtained with Labrasol microemulsion was higher than with other surfactants (8.4 % for Tween 80 and 3.4 % for Transcutol P). Additionally, in vitro permeation studies demonstrated that Labrasol also inhibited the intestinal secretory transport. The effect of Labrasol is ascribed to both (1) enhanced GM absorption from the GI lumen into the systemic circulation and (2) inhibition of efflux of GM from the enterocytes to the GI lumen.
Spectral properties and ionization behavior of retinoids II. Bile salt solutions
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Purpose: The spectral properties and ionization behavior of retinoic acid (RA) and three structurally related arotinoids, MTTO, TTNPB, and TTNN, have been determined in simple micellar and mixed micellar solutions to provide a better understanding of the intestinal absorption of retinoids. Methods: Spectrophotometric and pH measurements have been made to determine the ionization constant in bile salt solutions. The fluorescent intensity and polarization of TTNN was determined. The extent of solubilization of retinoic acid in 10 mM NaTC/10 mM egg PC solutions was determined as a function of pH. Results: The rank order of wavelengths of maximum absorption, λ_max, was as follows: aqueous solution>dihydroxy bile salt>trihydroxy bile salt>ethanol>mixed micelles. The interaction as reflected in the λ_max of arotinoids with the bile salts at low pH depended on the mixing order, but this was not the case for retinoic acid. The rank order of the observed negative logarithm of the ionization constants, pK_{a_obs}, was aqueous solution>mixed micelles>dihydroxy bile salt>trihydroxy bile salt which reflects both the polarity as well as the electrostatic charge of the aggregates. The calculated electrostatic and dielectric effects on the ionization constant were comparable in bile salt micelles suggesting that TTNN is repositioned with a change in the ionic strength and that the size distribution of bile salt simple micelles appears to be perturbed by the presence of TTNN. In addition, the size of the bile salt-TTNN aggregate was independent of ionic strength and the type of bile salt. The solubilization of retinoic acid in bile salt/egg PC mixed micelle does not follow the expected dependence of pH indicating the presence of specific interactions. Conclusions: Retinoic acid and its derivatives exist almost exclusively in aggregated forms with RA forming a distinct type of aggregate in comparison to the arotinoids. The values of the pK_{a_obs} of the retinoids ranged from near 5 in simple bile salt aggregates to >7 in self-associated aggregates and mixed micelles which reflects the sensitivity of the ionization to the environment. This sensitivity has direct implications for the extent solubilized in the intestine and thereby complicates efforts at understanding the mechanism of the oral absorption of retinoids.
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^⊗: Abstract published in Advance ACS Abstracts, September 1, 1995.

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Retinoid Absorption from Simple and Mixed Micelles in the Rat Intestine⊗

Abstract

Ann. Oncol

Am. J. Med

J. Am. Acad. Dermatol

Prev. Med

Lipid Res

J. Chromatogr

J. Chromatogr

Int. J. Pharm

J. Lipid Res

Gastroenterol

Biochim. Biophys. Acta

Gastroenterol

Am. J. Physiol

Pharmacobio-Dyn

Lipids

J.Pharm. Sci

J. Am. Oil Chem. Soc

Biochemistry