Administration routes bioavailability

For all extravascular administration routes, bioavailability is determined by the following two sequential processes (see Fig. 17.1) ... 

In recent years, much of the research work in the pharmaceutical sciences was focused on the development of effective vehicle systems, such as micelles, microemulsions, and liposomes, for drugs that are critical with respect to bioavailability. Knowledge of this subject is a prerequisite to developing vehicle systems for special administration routes, such as dermal, transdermal, intravenous, and nasal. 

Sasaki, K., et al. 2003. Improvement in the bioavailability of poorly absorbed glycyrrhizin via various non-vascular administration routes in rats. Int J Pharm 265 95. 

Zolpidem is rapidly absorbed after oral administration. Its bioavailability is approximately 70 %. Peak plasma concentrations are attained 1.0-1.5 h after a single therapeutic dose of 10 mg. The major metabolic routes in man include oxidation and hydroxylation, and none of the metabolites is pharmacologically active. The mean ti/2 of zolpidem in healthy volunteers is 2.0-2.5 h [27] (Tab. 2). 

Most peptides and proteins are currently formulated as parenteral formulations because of their poor oral bioavailability. Nevertheless, oral delivery of peptides and proteins would be the preferred route of administration if bioavailability issues could be overcome, as it offers the advantages of convenient, pain-free administration. Although various factors such as permeability, chemical and metabolic stability and gastrointestinal transit time can affect the rate and extent of absorption of orally administered peptides and proteins, molecular size is generally considered the ultimate obstacle [36]. 

A -tetrahydrocannabinol is a liquid and is highly insoluble in water (8-10). This can be a critical factor in its bioavailability, pharmacokinetics and pharmacological action. Large differences in the bioavailability of tetrahydrocannabinol from various solutions and administrative routes have been reported (9,10). Evidence has been presented (8) that tetrahydrocannabinol s solubility may be exceeded in plasma, resulting in its possible precipitation and fortuitous localized accumulation in body organs. 

In contrast, Absolute Bioavailability involves comparison of the chug s bioavailability with respect to the corresponding bioavailability after iv administration. Absolute bioavailability may be calculated by comparing the total area under the Cp vs T curve obtained from the absorption route in question (often the oral route, although the approach can be used for other routes, such as the nasal, buccal, transdermal routes etc ), with that of the Cp vs T curve following iv administration ... 

Dry powder formulations for nasal delivery of peptides and proteins have been investigated for the first time by Nagai and others [38], Since then, much research work has been done on dry powders containing bioadhesive polymers for nasal drug administration. The bioavailability and duration of action of drugs administered by the nasal route are increased by the use of the principle of mucoadhesion and dry powder formulations. Research work on dry powder formulation containing bioadhesive polymers is summarized in Table 1. 

Ondansetron (OND), a. S-hydroxytryptaminej receptor antagonist, has been used for prevention of nausea and vomiting associated with emetogenic cancer therapy. In view of the condition being treated, intravenous and oral dosage forms of OND may be inconvenient and/or unfeasible for specific patient populations. The nasal cavity can be a potential alternative route. A dose of 1 mg/kg OND (Zofran injection, 2 mg/mL) was administered to male Sprague-Dawley rats intravenously or intranasally. The peak plasma level of OND was attained within 10 min after application to the nasal mucosa of the rat. The plasma concentration-time profiles for nasal administration were comparable to those for intravenous injection, indicating complete absorption via the nasal route. The terminal elimination half-lives of the two routes of administration were also similar. The nasal administration route of OND was superior to the oral route (in humans, the oral absolute bioavailability is only 56% and the time to peak concentration is 1.0-2.Ih) and as effective as the intravenous route. 

To express the extent to which and at what rate a drug reaches the systemic circulation, the term bioavailability is used. Bioavailability of a drug is (1) the fraction of the administered dose which reaches the systemic circulation and (2) the rate at which this occurs. After intravenous administration bioavailability is by definition 100% for all other routes of administration, the bioavailability can vary between 0 and 100%. 

As for a formulation using another administration route, Leitner et al. developed a nasal delivery system of hGH [194] based on the thiomer polycarbophil-cysteine (PCP-Cys) in combination with the permeation mediator glutathione (GSH). Microparticles were prepared by dissolving PCP-Cys/GSH/hGH (7.5 1 1.5), PCP/ hGH (8.5 1.5), and mannitol/hGH (8.5 1.5) in demineralized water, followed by lyophilization and micronization. PCP-Cys/GSH/hGH and PCP/hGH microparticles showed a comparable size distribution (80% in the range of 4.8 to 23 pm) and swelled to almost four fold size in phosphate-buffered saline. Both formulations exhibited almost identical sustained drug release prohles. The intranasal administration of the PCP-Cys/GSH/hGH microparticulate formulation resulted in a relative bioavailability of 8.11%, which represents a three fold and a 3.3-fold improvement compared with that of PCP/hGH microparticles and mannitol/hGH powder, respectively. The nasal microparticulate formulation based on PCP-Cys/ GSH/hGH might represent a promising novel tool for the systemic delivery of hGH. 

Usually, desmopressin is administered intranasally by use of sprays or drops. This administration route of desmopressin was considered to be more efficacious than the oral route, because bypassing the gastrointestinal tract increases the absolute bioavailability from less than 1% to approximately 5%. However, nasal application of desmopressin is accompanied by high intersubject and intrasubject variability in plasma pharmacokinetics [215]. Therefore, there have been several pharmaceutical research efforts to improve nasal delivery of desmopressin. 

The lack of activity after oral administration for most peptides and proteins resulted in the past besides parenteral application into the utilization of nonoral administration pathways, for example, nasal, buccal, rectal, vaginal, percutaneous, ocular, or pulmonary drug delivery [27]. Drug delivery via these administration routes, however, is also frequently accompanied by presystemic degradation processes. Bioavailability of numerous peptides and proteins is, for example, markedly reduced after subcutaneous or intramuscular administration compared to their intravenous administration. The pharma-cokinetically derived apparent absorption rate constant is thus the combination of absorption into the systemic circulation and presystemic degradation at the absorption... 

Melendez-Alafort L, Riondato M, Nadali A, Banzato A, Camporese D, Boccaccio P, Uzunov N, Rosato A, Mazzi U. Bioavailability of 99mTc-HA-paclitaxel complex [99mTc-ONCOFID-P] in mice using four different administration routes. J Labelled Comp Radiopharm 2006 49 939-950. 

Bioavailability Percent absorbed into systemic circulation after administration o Bioavailability depends on route of administration as well as the... 

The oral route is undoubtedly the most widely investigated alternative administration route however, it presents major concerns in the delivery of macromolecular actives. The gastrointestinal route can promote degradation in the stomach due to the acidic gastric pH. The intestine has issues arising from the presence of proteolytic enzymes and insufficient permeation toward these actives, all of which result in limited bioavailability. Therefore, other routes of delivery have been investigated and the oral mucosal route presents a convenient alternative. 

However, the remaining problem was the administration route of the drug. Shortly before the Second World War, Inhoffen had prepared 17a-ethynyl-oestradiol, and had noticed that this derivative is surprisingly stable in the stomach. The initial objective of Inhoffen s synthesis was actually oestradiol-17-car-boxylic acid, which ought to have been produced by ethynylation and ozonoly-sis. Fortunately, the intermediate was also checked for its oral bioavailability. In fact, the carboxylic acid was only synthesised 50 years later and proved to be completely inactive. [24]... 

The nasal administration was shown to be an effective administration route for lipophilic active substances like fentanyl. Moreover, the nasal route has also been used for the systemic administration of small peptides like buserelin acetate, nafarelin acetate and desmopressin, aU of them containing ten or less amino acid residues. However, for these molecules the nasal route forms only a poor non-invasive alternative to injection, since the nasal bioavailability of these peptides is less than 3-5 %. 

These four actions are subsequently discussed in this chapter with an emphasis on pharmacy preparations. In addition to pharmaceutical aspects, selection of a suitable administration route and specific bioavailability considerations were recognised as relevant input variables in formulation design. 

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