Intestinal Absorption of Drugs. The Influence of Mixed Micelles on on the Disappearance Kinetics of Drugs from the Small Intestine of the Rat

Abstract

The solubilization of the hydrophilic drugs paracetamol and theophylline, and the lipophilic drugs dantrolene, griseofulvin and ketoconazole has been determined in mixed micellar aqueous dispersions composed of 10 mM taurocholate + 5 mM oleic acid. The solubilization of dantrolene and paracetamol has also been determined in aqueous (mixed) micellar dispersions of 1 g L-1 lysophosphatidyl-choline (LPC), or taurocholate/LPC. The influence of these (mixed) micelles on the absorption of the model drugs from solution was studied in the rat chronically isolated internal loop. Absorption kinetics of the drugs were evaluated on the basis of the disappearance rate of the drug dissolved in the perfusion medium in this loop. Absorption experiments with taurocholate/oleic acid in the perfusate resulted in a reduction of the disappearance rate for the lipophilic drugs and the hydrophilic drug theophylline. This could partly be ascribed to the decreased fraction of drug free in solution as a result of its micellar solubilization for dantrolene, griseofulvin and ketoconazole, but the decrease in the disappearance rate of theophylline was unexpected. Taurocholate/oleic acid, LPC and taurocholate/LPC micelles had no effect on the disappearance of paracetamol. The disappearance rate of dantrolene in the presence of LPC alone was not altered, in spite of the decreased fraction of the drug free in solution owing to its micellar solubilization. In contrast, taurocholate/LPC micelles caused a reduction in the rate of disappearance of dantrolene, as expected according to the phase-separation model. In-vitro, taurocholate and taurocholate/LPC reduced the molecular cohesion of porcine intestinal mucus, whereas LPC alone did not exhibit an effect on the gel structure of mucus.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats

“…The reduction in the absorption kinetics of lipophilic drugs in the presence of sodium taurocholate was partly ascribed to the reduction of the free drug fraction due to micellar solubilization (Poelma et al, 1990).…”

The Solubility–Permeability Interplay and Its Implications in Formulation Design and Development for Poorly Soluble Drugs

“…Previous studies have shown that the use of surfactants may lead to increased, decreased, or unchanged membrane permeability (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). It is important to note that surfactants may increase intestinal membrane permeability for drugs with inherently low-permeability and high aqueous solubility (i.e., BCS class III compounds), e.g., through the disruption of membrane integrity to increase paracellular transport (e.g., tight junction opening, which may induce potentially toxic effects) and/or the inhibition of efflux transporters (36,39,(42)(43)(44)(45).…”

“…It is important to note that surfactants may increase intestinal membrane permeability for drugs with inherently low-permeability and high aqueous solubility (i.e., BCS class III compounds), e.g., through the disruption of membrane integrity to increase paracellular transport (e.g., tight junction opening, which may induce potentially toxic effects) and/or the inhibition of efflux transporters (36,39,(42)(43)(44)(45). However, for lipophilic drugs with inherently high transcellular membrane permeability (e.g., BCS class II), surfactants can decrease the free fraction of drug which results in decreased intestinal membrane permeability (31,35,(39)(40)(41)(42).…”

Development and optimization of self microemulsifying drug delivery of domperidone

“…Further, the SMEDDS is believed to increase oral absorption via any of the following mechanisms: (a) Retardation of gastric transit time, (b) increase in effective drug solubility in lumen (c), lymphatic transport of the drug, (d) enterocyte based drug transport and, (e) increasing membrane permeability (Poelma, Breãs. Tukker, 1990;Poelma et al, 1991;Shah et al, 1994;Porter, Charman, 2001;Porter, Trevaskis, Charman, 2007).This facet of SMEDDS makes them stand alone in the category of oral lipid based formulations. Several SMEDDS of BCS class II drugs i.e.…”