Rectal drug absorption surfactants

The absorption of drugs from the rectal [32] cavity has been studied in some detail. Muranishi et al. [34] have shown that a significant increase in the absorption and lymphatic uptake of soluble and colloidal macromolecules can be achieved by pretreating the rectal mucosal membrane with lipid-nonionic surfactant mixed micelles. They found no evidence of serious damage of the mucosal membrane. Davis [30] suggested that the vaginal cavity could be an effective delivery site for certain pharmaceuticals, such as calcitonin, used for the treatment of postmenopausal osteoporosis. 

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

In the past two decades, many studies have tested adjuvants that act by either permeabilizing the rectal mucosa or inhibiting drug degradation. Oral and rectal routes of drug administration are unsuitable for adequate absorption of various compounds with a peptide or protein structure and of several hydrophilic antibiotics. The use of absorption enhancers, e.g., salicylates, enamines, surfactants, and straight-chain fatty acids, has gained wide interest... 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

Sekine, M., et al. 1985. Improvement of bioavailability of poorly absorbed drugs. V. Effect of surfactants on the promoting effect of medium chain glyceride for the rectal absorption of (3-lactam antibiotics in rats and dogs. J Pharmacobiodyn 8 653. 

Rectal absorption of drugs from aqueous or alcoholic solutions is generally much faster than from suppositories. Non-surfactant adjuvants, such as salicylates, increase rectal absorption of water-soluble drugs and also of high molecular weight compounds, such as insulin, heparin, and gastrin. 

The inclusion of a surfactant in the suppository formulation may enhance the rectal absorption of drugs. The effect has been attributed to the formation of mixed micelles. It has been suggested that the presence of the micelle facilitates the incorporation of the lipid component of the mixed micelle into the biological membrane. This lipid then enhances the fluidity and permeability of the membrane to the poorly absorbed drug. It appears that the colorectal mucous membrane is more sensitive to the effects of mixed micelles than the gastrointestinal membrane of the small intestine. 

Drug Interactions and Availability - The role of surfactants in modifying the availability and/or the absorbability of various barbiturates via the rectal route was the subject of a report by Fincher, Entrekin, and Hartman.These workers, employing a petrolatum-paraffin base suppository, added various surfactants of known HLB values, and determined the effect of the incorporated barbiturate on the rate of respiration of the rabbit. The authors concluded that while the inclusion of a surfactant enhanced the rate of absorption of the barbiturates in some cases, it could also bind the drug, thus making it less available for the absorption process. 

NB By extrapolation of apparent values to 0% 7-(2-hydroxypropyl)-theophylline that was used as a complexing agent to increase solubility. TRIS was used as a pKg reference (pKa = 8.18 at 20 C). See also Ritschel, who cited Fincher JH, Entrekin DN, Hartman CW, Surfactant-Base-Barbiturate Suppositories I Rectal absorption in rabbits, J. Pharm. Sci., 55,23-28 (1966). Fincher in turn cited values from Shanker LS, Absorption of drugs from the rat colon, JPET, 126,283-290 (1959) for 4 cpds 5-allyl-5-isobutylbarbituric acid (7.86) 5-butyl-5-ethylbarbituric acid (8.10) 5-efhyl-5-(l-mefiiylbutyl)barbituric acid (8.17) and 5-allyl-5-isopropylbarbituric acid (7.54). 

The behaviour of sulphisoxazole in surfactant and glycol solutions has been studied in a series of papers [140,141]. In order to clarify the mechanism of the reduction in rectal absorption of this sulphonamide in the presence of PEG 4000 the effect of this compound on its physicochemical properties was examined. There is a linear relationship between the solubilities of sulphathiazole, sulphapyridine, and sulphisoxazole and the concentration of PEG 4000. The drugs apparently do not form complexes with the glycols it is thought that the reduction in activity is due to a depression of the concentration of the drug in rectal lipid. The effect of non-ionic surfactants is to reduce the absorption of the sulphonamides through solubilization in micelles [141]. Fig. 6.18 indicates the extent of solubilization in polysorbate 80 solutions. Values of apparent distri-... 

Sodium salicylate has been found to enhance rectal absorption of drugs [309] but contrary to the action of some surfactants the absorption promotion was not found to be the result of a permanent change in the rectal mucosa. 

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