Rectal absorption

Due to a combination of poor membrane permeability and metabolism at the site of absorption, rectal bioavailability of peptide and proteins is low. As in other mucosal bioavailability testing, insulin is the most studied polypeptide with respect to rectal absorption. 

Less absorption rectally than orally because the absorbing surface area of the rectum is smaller... 

This model is representative for the conditions described in the previous section, except for the mode of administration which can be oral, rectal or parenteral by means of injection into muscle, fat, under the skin, etc. (Fig. 39.7). In addition to the central plasma compartment, the model involves an absorption compartment to which the drug is rapidly delivered. This may be to the gut in the case of tablets, syrups and suppositories or into adipose, muscle or skin tissues in the case of injections. The transport from the absorption site to the central compartment is assumed to be one-way and governed by the transfer constant (Fig. 39.7a). The linear differential model for this problem can be defined in the following way ... 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

Intestinal surface area and total blood flow to the GIT are smaller than in adults and may influence the efficiency of absorption. With regard to the use of rectal suppositories, one must keep in mind that the completeness of absorption will be a function of retention time in the rectum. Since bowel movements in... 

S Riegelman, WJ Crowell. The kinetics of rectal absorption. III. The absorption of undissociated molecules. J Am Pharm Assoc Sci Ed 47 127-133, 1958. 

K Kakemi, T Arita, S Muranishi. Absorption and excretion of drugs. XXVII. Effect of nonionic surface-active agents on rectal absorption of sulfonamides. Chem Pllarm Bull 13 976-985, 1965. 

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. 

M. Murakami, Enhanced absorption and lymphatic transport of macromolecules via the rectal route, in Delivery Systems for Peptide Drugs (S. S. Davis, L. Ilium, and E. Tomlinson, eds.), Plenum Press, New York, 1986, p. 177. 

Rectal Administration. The administration of drugs by a solid rectal dosage form (i.e., suppositories) results in a wide variability in the rate and extent of absorption in children [79]. This fact, coupled with the inflexibility of a fixed dose, makes this a route that should not be promoted for pediatric patients. At least one death involving a 7-month-old infant can be directly attributed to the use of solid rectal dosage form of a therapeutic dose of morphine [80]. 

M. Nowak, B. Brundhofer, and M. Gibaldi, Rectal absorption from aspirin suppositories in children and adults, Pediatrics, 54, 23 (1974). 

Possible noninvasive routes for delivery of proteins include nasal, buccal, rectal, vaginal, transdermal, ocular, oral, and pulmonary. For each route of delivery there are two potential barriers to absorption permeability and enzymatic barriers. All of the... 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

AJ Repta. Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption. Pharm Res 6(6) 501-505, 1989. 

H Sandberg-Gretzen, M Ryde, G Jarnerot. Absorption and excretion of azodisal sodium and its metabolites in man after rectal administration of a single 2-g dose. Scan J Gastroenterol 18 571-575, 1983. 

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-... 

T Murakami, Y Sasaki, R Yamajo, N Yata. (1984). Effect of bile salt on the rectal absorption of sodium ampicillin in rats. Chem Pharm Bull 32 1948-1955. 

BJ Aungst, NJ Rogers, E Shefter. (1988). Comparison of nasal, rectal, buccal, sublingual, and intramuscular insulin efficacy and the effects of a bile salt absorption promoter. J Pharmacol Exp Therap 244 23-27. 

Lennernas, H., Gjellan, K., Hallgren, R., Graffner, C., The influence of caprate on rectal absorption of phenoxymethyl-penicillin experience from an in-vivo perfusion in humans, J. Pharm. Pharmacol. 2002, 54, 499-508. 

Raab, Y., Gerdin, B., Hallgren, R., Regional rectal perfusion a new in vivo approach to study rectal drug absorption in man, Pharm. Res. 1995, 12, 426-432. 

The sodium salt of the phenylglycine derivative (33) was investigated as an absorption promoter for the rectal absorption of beta-lactam antibiotics and insulin [80JAP(K)31040 81CPB1998, 81CPB2012], (Naphthothiazol-2-ylidene)malonates (1661 and 1662) were applied in silver halide photographic emulsions as sensitizer dyes [82JAP(K)54936]. 

A review of GI transit and oral drug absorption can be organized in many ways, but a logical sequence is to start at the top and work down. In this review, techniques to study buccal and rectal delivery will not be covered, but a detailed description of these is available in a recent book (1). 

Aungst BJ, Rogers NJ (1988a) Site dependence of absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin on rectal, nasal, and buccal insulin delivery. Pharm Res 5 305-308... 

Similarly, the 4-methoxy-2-naphthylamides of Leu, Ala, Arg, and Glu (6.1, R=side chain of amino acid, R =MeO) were used to assess the type and activity of aminopeptidase in homogenates of conjunctival, nasal, buccal, duodenal, ileal, rectal, and vaginal tissues from rabbits. This systematic comparison afforded a better understanding of the role of the aminopeptidase barrier in peptide absorption from oral vs. non-oral routes [18]. In a comparable manner, the y-glutamyltranspeptidase and dipeptidase activities were investigated in mammary tissue with the 4-nitroanilides of Leu, Met, Lys, Glu, and Asp (6.2, R=side chain of amino acid) [19]. 

Rectal Administration Rectal administration of a drug may be applied when the patient is unable to take the drug orally and some other routes are impractical. The drug administered via the rectum is absorbed and partially bypasses the liver. However, the absorption of drugs may be unreliable in certain cases. 

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