Figure 7.14 Plasma concentration versus time curves of 250 mg diflunisal after oral administration as a suspension in water (•) and after rectal administration in methylcellulose solution at pH 4.5 (□) and 7 (■)
pH to 7.0. Control of pH appears to be important to optimize the solubility of a number of drugs; for example codeine, when delivered in solution at pH 9, produced better absorption than at pH 4.3139. When delivered in 'Witepsol' H15, codeine phosphate can exhibit a plasma concentration profile almost identical to the oral formulation140.
Natural or hydrogenated soya lecithin added to diclofenac suppositories prolonged absorption from about 1 h to 6 h in healthy volunteers, without affecting the extent of absorption141. Interestingly, this study reported that absorption was not affected by defaecation.
Orally administered antiemetics suffer from quite obvious drawbacks and hence rectal administration of alizapride, promethazine and metoclopramide have been investigated. Rectal administration of alizapride as a suppository in an unspecified base resulted in a mean bioavailability of 61% relative to an intravenous bolus dose142. Both alizapride and promethazine have considerably slower absorption profiles from rectal administration compared to either oral or intramuscular administration. In addition, promethazine produces significant rectal irritation.
In human subjects, an aqueous microenema containing metoclopramide resulted in rapid absorption and complete absolute bioavailability. Another advantage of delivering metoclopramide rectally is that when given orally, it undergoes extensive first-pass metabolism.
Metronidazole is used extensively in the prophylaxis and treatment of anaerobic infections. For practical and economical reasons, attempts have been made to develop rectal metronidazole formulations. It is absorbed rapidly but incompletely from aqueous suspension formulations.
Ampicillin is poorly absorbed from the rectum and despite many formulation attempts, currently the problem has not been overcome. In addition the drug can produce mucosal irritation and diarrhoea.
Theophylline absorption from a rectal solution is similar to absorption from oral solutions, and generally occurs rapidly and completely. However, absorption from suppositories may be variable and incomplete. Interestingly, theophylline was well absorbed when delivered in a rectal osmotic delivery device, despite the fact that the level of water available in the rectum is very low143.
The absorption of enprofylline, a bronchodilating xanthine drug which is poorly metabolised, shows somewhat slow absorption from rectal administration of an aqueous solution compared with oral intake. Oral absorption was complete, whereas urinary data indicated an absolute rectal bioavailability of about 89%144.
Mesalazine is the locally active moiety of sulphasalazine used in the treatment of inflammatory bowel disease. It is liberated from the orally administered parent drug in the colon by bacterial splitting of an azo bond. It is frequently delivered by enema, particularly in patients with ulcerative colitis of the distal colon. As the adverse effects of oral sulphasalazine are ascribed to the sulphapyridine moiety, colon specific formulations have been developed which have low systemic bioavailability without the sulphapyridine group.
Rectal instillation of corticosteroids is a well-established approach for the treatment of inflammatory bowel disease. Corticosteroids which show high efficacy and low systemic drug concentrations are preferred, in order to minimise adrenal suppression and other adverse effects inherent in steroid therapy. Rectal prednisolone, budesonide, tixocortol pivalate and beclomethasone diproprionate appear to interfere less with adrenocortical function than hydrocortisone acetate, prednisolone-21-phosphate and betamethasone. In clinical practice, steroid enemas prove to be difficult to retain because of their large volume, and hence foams are used.
Rate-controlled rectal drug delivery of nifedipine by an osmotic delivery device in healthy volunteers resulted in a steady-state plasma concentration, with the low input rate resulting in a lowering of blood pressure without concurrent reflex tachycardia.
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