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Abstract

The influence of sodium taurocholate (TC) on the intestinal absorption of drugs was studied in vivo in a chronically isolated internal loop in the rat. The hydrophilic drugs paracetamol (PA) and theophylline (TP) and the lipophilic drugs griseofulvin (GF) and ketoconazole (KE) were used as model drugs. The drug concentrations were kept below the saturation concentration. Absorption kinetics of the drugs were evaluated on the basis of disappearance rates of the drug from luminal solutions in the intestinal loop. Concentrations of TC above the critical micelle concentration (CMC) did not affect the absorption rate of the hydrophilic drugs PA and TP; the barrier function of the intestinal wall for PA and TP was not altered in the presence of taurocholate. The addition of concentrations of TC above the CMC in the perfusion solution resulted in a reduction of the absorption rate of GF and KE. The reduction in the absorption kinetics of GF in the presence of TC correlated well with the reduction of the drug-free fraction in solution due to micellar solubilization. For KE this relation was less clear. It was not possible to determine, on the basis of the phase-separation model, to what extent the fraction of the drug incorporated in TC micelles contributes to the overall diffusion of GF and KE across the preepithelial diffusion barrier. It was concluded that TC exhibits only a minor, if not negligible, effect on the barrier function of the aqueous diffusion barrier adjacent to the intestinal wall.

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

“…However, the micellar solubilization which gives rise to this important apparent solubility enhancement also results in decreased free fraction of drug. Similar to the case of cyclodextrins, this incorporation of drug in micelles significantly decreases the amount of free drug available for permeation through the intestinal membrane (31,32,34,35,(40)(41)(42).…”

“…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).…”

Influence of D-Glucose-lnduced Water Absorption on Rat Jejunal Uptake of Two Passively Absorbed Drugs

“…In Situ Rat P e r f u s i o e M a l e Sprague-Dawley rats from Charles River Breeding Laboratories (Wilmington, MA), weighing 300-350 g, were fasted overnight (16)(17)(18)(19)(20) h) prior to inducing anesthesia by im injection of 1.5 g k g body weight of urethane (ethyl carbamate; Sigma). Following anesthesia, rats were put on a heating pad and under a heating lamp to maintain body temperature.…”

Physicochemical and Physiological Mechanisms for the Effects of Food on Drug Absorption: The Role of Lipids and pH

“…The effect of bile salts on the intestinal absorption of model hydrophilic (paracetamol and theophylline) and lipophilic drugs (griseofulvin, ketaconazole, and dantrolene) was studied by Poelma et al 96,97 using a rat in situ intestinal perfusion technique. Simple or mixed bile salt micelles had no effect on absorption of the hydrophilic drugs, leading to the conclusion that bile salt micelles had minimal effect on the intrinsic barrier function of either the UWL or the intestinal membrane.…”