Oral bioavailability improvement

Pharmacokinetics attd Pharmacology. Older macrolides such as erythromycin exhibit relatively low serum concentrations, short in vivo half-hves, highly variable oral absorption, and low oral bioavailability. Improvements in these pharmacokinetic parameters have been accomplished for newer derivatives. The principal side effects of macrolides aie gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. 

Oomen AG, Brandon EFA, Swartjes FA, Sips AJAM. 2006. How can information on oral bioavailability improve human health risk assessment for lead-contaminated soils Implementation and scientific basis. Bilthoven RIVM. RIVM report 711701042. Available from . 

One of the most popular orally active penicillins in present clinical use is amoxicillin (12). Its oral effectiveness and broad spectrum of activity against common pathogens as well as its better absorption than its closest precedent competitor, ampicillin (14), largely accounts for this. Higher blood and tissue levels of antibiotics is another means of dealing with resistance. In an attempt to achieve yet further improvements in oral bioavailability and hence blood and ti.ssue levels of amoxicillin, the prodmg fumoxicillin (13) is prepared from amoxicillin (12) by treatment with furfural [3]. The imine moiety is less basic than the primary amine so that the isoelectric point of fumoxicillin is more on the acid side than is that of amoxicillin. 

Most ACE inhibitors are prodrugs, with the exceptions of captopril, lisinopril, and ceranapril. Prodrugs exert improved oral bioavailability, but need to be converted to active compounds in the liver, kidney, and/or intestinal tract. In effect, converting enzyme inhibitors have quite different kinetic profiles with regard to half time, onset and duration of action, or tissue penetration. 

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

Another new development has been the application of oral absorption promoters. These materials are designed to enhance the oral bioavailability of many compounds and improve variable absorption. However, many of these compounds are hydrophobic in nature and cause difficulty during tableting itself. The challenge for formulators is to arrive at clever solutions to the process problems while retaining material performance. 

Alkoxyalkanoate esters have been used as prodrugs to improve the oral bioavailability of antiviral agents such as (+)-cyclaradine (carbocyclic arabino-furanosyl adenine) [41]. (+)-Cyclaradine has been shown to be effective against herpes simplex virus in tissue culture at noncytotoxic concentrations. Two prodrugs of (+)-cyclaradine, namely, (+)-cyclaradine-5 -methoxyacetate (CM) and (+)-cyclaradine-5,-ethoxypropionate (CE) (Fig. 2), may be promising candidates... 

Some drugs with low intrinsic permeability achieve acceptable oral bioavailability because they are substrates for uptake transporters, which normally function in nutrient uptake. The most prominent example is the peptide transporter, PepTl, which is active toward peptidomimetic antibiotics such as cephalexin, the antiviral agent valacyclovir [24] and other drugs. PepTl is natively expressed in Caco-2 cells, and adenovirus transduction has been used to increase PepTl expression levels [25]. However, the expression of PepTl was not polarized in this system and this expressed system appears to be of limited value as an improved screening model. PepTl has also been expressed in Chinese hamster ovary cells and a variety of other mammalian systems [26, 27]. 

Further analysis yielded new models for each of the chemical classes with improved statistical significance. The final model for nonaromatics contained six descriptors and had an Rs of 0.932 (leave-one-out 0.878), the final model for the aromatics contained 21 descriptors and had an Rs of 0.942 (leave-one-out 0.823), and the final model for the heteroaromatics contained 13 descriptors and had an Rs value of 0.863 (leave-one-out 0.758). These statistical results were considered reliable enough for the models to be regarded as predictive. The analysis did yield some interesting insights into the impact of various structural fragments on human oral bioavailability. However, these observations were based on the sign of the coefficient and so must be treated with some caution. 

Genetic programming, a specific form of evolutionary computing, has recently been used for predicting oral bioavailability [23], The results show a slight improvement compared with the ORMUCS Yoshida-Topliss approach. This supervised learning method and other described methods demonstrate that at least qualitative (binned) predictions of oral bioavailability seem tractable directly from the structure. 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Second-generation triptans (all except sumatriptan) have higher oral bioavailability and longer half-lives than oral sumatriptan, which could theoretically improve within-patient treatment consistency and reduce headache recurrence. However, comparative clinical trials are necessary to determine their relative efficacy. 

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