Rationale

Why Maximize Oral Bioavailability?

One of the most important pharmacokinetic characteristics of a drug or new drug candidate is its oral bioavailability. The oral route is the preferred means of administration for most drug therapies, particularly those self-administered by the patient on an ongoing basis. Unless a drug is intended to treat a condition of the gastrointestinal tract, its effectiveness after oral administration requires attaining adequate and consistent systemic exposure. The extent of bioavailability determines the levels of exposure as well as the variability in exposure. Hellriegel et al. (1996) surveyed 143 literature references reporting absolute oral bioavail-ability and described the relationship between absolute bioavailability and inter-subject variability (% CV) for 100 drugs studied in those references. It was shown that the variability of systemic exposure after oral dosing was greatest when oral bioavailability was low and, conversely, inter-subject variability was generally low when oral bioavailability was high. Variability of systemic exposure leads to inconsistent and possibly unpredictable pharmacological and toxicological effects of the drug. Therefore, drugs with good oral bioavailability can have a considerable therapeutic advantage over related drugs with poor oral bioavailability.

If a drug is subject to extensive presystemic metabolism, it is likely that there will be high levels of metabolites generated and appearing in the systemic circulation. These metabolites may have pharmacologic effects or unwanted side effects. Another reason to strive for the greatest bioavailability is to reduce the exposure to metabolites and to limit the effects caused by metabolites. For example, oral administration of oxybutynin resulted in plasma AUC of des-ethyl-oxybutynin more than 10-fold greater than the plasma AUC of oxybutynin. Following oxybutynin administration using an alternative delivery method that reduced the extent of presystemic metabolism, the plasma AUC of the metabolite was only 2-fold greater than that of oxybutynin, and fewer systemic side effects resulted (Buyse et al.,1998). Similarly, Clarke et al. (2003) showed that plasma concentrations of selegiline metabolites were significantly reduced when selegiline was administered using a transmucosal delivery system, which increased selegiline bioavailability relative to oral administration and afforded a potentially safer and more predictable method for treatment of Parkinson's disease.

A third reason to maximize oral bioavailability is related to the efficiency of use of the active drug substance. If oral bioavailability averages 25% (25% of the dose reaching the systemic circulation intact), then 75% of the active drug substance is wasted. This inefficiency of compound usage adds to the cost of the pharmaceutical product and can be an especially important factor for active drug ingredients that are expensive to produce. For these reasons, enormous efforts are made to identify new drug candidates that have reasonably good oral bioavail-ability in animal models and in humans. Similarly, existing drugs with less than optimal oral bioavailability represent an opportunity for technologies that afford improved drug delivery.

Incomplete oral bioavailability can be caused by incomplete absorption from the intestinal tract, due to solubility or permeability limitations, or can be related to presystemic metabolism. Presystemic metabolism is typically due to hepatic extraction, although recently the role of intestinal metabolism has become increasingly recognized. Incomplete oral bioavailability due to incomplete absorption can often be addressed with formulation modifications. However, there is no formulation solution to overcome hepatic first-pass metabolism. The chemical approach is required, and often times the prodrug approach has been utilized, especially when chemistry has been optimized for the desired pharmacological properties. This chapter reviews the application of prodrug strategies aimed at improving oral bioavailability by reducing presystemic metabolism.

The Prodrug Approach

Systemic absorption after oral dosing requires the compound to pass through a series of potential sites of metabolism—the intestinal lumen, the intestinal epithelium, and the liver. If the structural position at which presystemic metabolism of a drug occurs is known and if presystemic metabolism is mediated primarily by a single enzymatic reaction at a single site of the molecule, then it may be possible to design prodrugs to block metabolism at that site. The prodrug is therefore intended to pass through the site of metabolism (intestinal membrane or liver) intact and then be hydrolyzed upon reaching the systemic circulation. An illustration of this prodrug strategy is given in Figure 1. One of the challenges in

Presystemic Metabolism

Presystemic Metabolism

Figure 1. Scheme describing the prodrug approach to reducing presystemic metabolism after oral administration.

Presystemic Metabolism

Figure 1. Scheme describing the prodrug approach to reducing presystemic metabolism after oral administration.

oral prodrug delivery is that there are multiple barriers, or potential sites of metabolism, in series. It is not unusual that a prodrug does not completely pass through the intestines and liver intact, because the intestines and liver generally have high levels of activity of the enzymes (e.g., esterases) generally mediating prodrug-to-active drug conversion. These potential pathways of prodrug disposition are also depicted in Figure 1 and will be discussed again later.

In this review, the presystemic metabolism of peptide drugs will also be considered. Peptide drugs have the additional barrier of degradation by digestive proteases and peptidases present in the intestinal lumen as well as on the brush border membrane of the enterocytes. Because of the high levels of these enzymes, transmucosal (e.g., nasal, buccal, rectal, or pulmonary) delivery may be more feasible than oral delivery for some biologically active peptides. However, these absorption sites may also be rich in peptidase enzyme activity. For example, certain peptides are rapidly degraded by aminopeptidases when exposed to the nasal mucosa. The prodrug approach can also be applied to the transmucosal delivery of peptide drugs that are highly metabolized by peptidases at the site of administration.

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