Bioavailability rectal

For drugs that have poor oral bioavailability, rectal administration of prodrugs can increase their absorption. For example, nalbuphine is an analgesic with potency approximately 0.5-0.9 that of morphine. It is used for the relief of moderate to severe pain from a variety of causes, e.g., surgery, trauma, cancer, kidney, or biliary colic pain. Oral bioavailability of nalbuphine was poor, e.g., around 6% in experimental dogs. Rectal administration of nalbuphine-3-acetylsalicylate in the same animals enhanced the bioavailability 4- to 5-fold to around 28%. In addition, the plasma half-life of nalbuphine after rectal administration of the prodrug was prolonged. 

A. G. De Boer, D. D. Breimer, H. Mattie, J. Pronk, and J. M. Gubbens-Stibbe, Rectal bioavailability of lidocaine in man Partial avoidance of first-pass metabolism, Clin. Pharmacol. Ther, 26, 701-709 (1979). 

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. 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

Sznitowska M. et al.. Bioavailability of diazepam from aqueous-organic solution, submicron emulsion and solid lipid nanoparticles after rectal administration in rabbits, Eur. J. Pharm. Biopharm., 52, 159, 2001. 

Phagocytosis rate increase. Polysaccharide fraction of the fruit, administered to adults at a concentration of 10 pg/mL, was active on polymorphonuclear leukocytes k Pharmacokinetics. Hexane extract of the fruit, administered rectally to 12 healthy male adults at a dose of 640 mg, produced bioavailability similar to that observed for the oral formulations. Extract, administered orally to healthy males at a dose of 320 mg (1 X 320 mg capsule, new formulation or 2 X 160 mg, reference preparation) for 1 month, produced a rapid absorption with a peak time (T J of 1.5-1.58 hour and peak plasma level (C J of 2.54-2.67 pg/mL. The area under the curve value ranged from 7.99 to 8.42 pg/hour/mL. The plasma concentration-time profile of both preparation was nearly identical. Both preparations can be considered as bioequivalenp Hexane ex-... 

Rectal bioavailability and pharmacokinetics. Serenoa repens extract, administered rectally to 12 healthy male volunteers at a dose of 640 mg/person, produced the mean maximum concentration in plasma of nearly 2.60 (Xg/mL approx 3 hours after administration, with mean value for the area under the curve AUC 10 (Xg/hour/mL. The bioavailability and pharmacokinetic profile were similar to those observed after oral administration. T j occurred approx 1 hour later, and plasma concentration 8 hours after drug administration was still quantified. The drug tolerability was good, and no adverse effect was observed ". Serenoa repens capsules, administered orally at a dose of 160 mg four times daily or rectally 640 mg daily for 30 days to 60 patients with BPH, produced no significant differences in diminu-... 

S.Tripodi. Rectal bioavailability and pharmacokinetics in healthy volun- SR079 teers of Serenoa repens new formulation. Arch Med Interna (Italy) 1994 ... 

Diazepam Potentiates GABAa responses Well absorbed orally rectal administration gives peak concentration in 1 h with 90% bioavailability IV for status epilepticus highly protein-bound extensively metabolized to several active metabolites tjy2 2 d Status epilepticus, seizure clusters Toxicity Sedation Interactions Minimal... 

Methadone has undergone a dramatic revival as a potent and clinically useful analgesic. It can be administered by the oral, intravenous, subcutaneous, spinal, and rectal routes. It is well absorbed from the gastrointestinal tract and its bioavailability far exceeds that of oral morphine. 

Pharmacokinetic properties Meptazinol has poor oral bioavailability due to extensive first-pass metabolism. Systemic availability is improved after rectal administration. Peak plasma concentrations are reached 30 min after rectal or intramuscular administration and plasma half-life is about 2 h. Plasma protein binding is low ( 30%). Meptazinole is extensively metabolized in the gut and liver mainly to the glucuronide derivative. Only about 10% is excreted unmetabolised in the faeces (Franklin, 1988). 

When utilized as sedative hypnotics, barbiturates are administered orally. They are rapidly and completely absorbed by this route with nearly 100% bioavailability and an onset of action ranging from 10 to 60 min.3 Sodium salts are more rapidly absorbed than free acids. Intramuscular injections of sodium salts should be made deep into the muscle to prevent pain and tissue damage. Some barbiturates are also administered rectally barbiturates utilized for the induction and maintenance of anesthesia (thiopental) or for treating status epilepticus (phenobarbital) are administered intravenously. 

Tramadol is available as drops, capsules, and sustained-release formulations for oral use, suppositories for rectal use, and solution for intramuscular, intravenous, and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 h, reach peak concentrations after 4.9 h, and have a bioavailability of 87 to 95% compared with capsules. One 100-mg dose given to healthy volunteers resulted in plasma levels of 375 ng/ml at 1.5 h.55 Tramadol is 20% bound to plasma protein and it is rapidly distributed in the body it is mainly metabolized by O- and A-demethylation forming glucuronides and sulfates that are excreted by the kidney. 

Certain kinds of improvements are possible in almost every dosage form. Besides oral and injectable formulations, CD inclusion has been shown to improve bioavailability of compounds administered by other routes, including ocular, topical, nasal, and rectal routes (Uekama et al., 1994 Marttin et al., 1998 Bary et al., 2001 Loftsson and Masson, 2001 Rode et al., 2003). Some important applications particularly applicable for insoluble compounds are summarized below. 

Many drugs can now be delivered rectally instead of by parenteral injection (intravenous route) or oral administration. Generally, the rectal delivery route is particularly suitable for pediatric and elderly patients who experience difficulty ingesting medication or who are unconscious. However, rectal bioavailabilities tend to be lower than the corresponding values of oral administration. The nature of the drug formulation has been shown to be an essential determinant of the rectal absorption profiles. The development of novel absorption enhancers with potential efficacy without mucosal irritation (low toxicity) is very important. The delivery of peptide and protein drugs by the rectal route is currently being explored and seems to be feasible. 

Watanabe, Y., et al. 1994. Bioavailability of gentamicin from a new rectal dosage vehicle in rabbtis. Yakuzaigaku 54 122. 

FIGURE 8.3 Bioavailability of morphine after rectal administrations of Witepsol H-15 hollow-type suppositories containing morphine hydrochloride (MH) and CyDs in rabbits. Each value represents the mean SE of three rabbits. p < 0.05, compared with MH alone. 

However, some negative effects of the combination of CyDs and polysaccharide on the rectal drug delivery were reported. Lin et al. [38] demonstrated that the mixture of (3-CyD and hydroxypropylmethylcellulose (HPMC) markedly reduced the in vivo bioavailability of acetaminophen from both aqueous solution and hydrogels. Not only the lower partition coefficient but also the higher hydrophilic property of the (3-CyD complex and the higher viscosity of HPMC hydrogel matrix might be responsible for the decrease in the in vitro permeation rate and depression of in vivo rectal absorption of acetaminophen. 

FIGURE 8.5 Possible enhancing mechanism of CyD for rectal bioavailability of water-insoluble drugs (a) and poorly absorbable drugs including peptide and protein (b). a, Stability constant. 

Surfactants are capable of improving various pharmaceutical properties such as wettability, solubility, dissolution rate, and miscibility, and are useful for improving the rectal bioavailability... 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

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