Optimizing the oral bioavailability

The optimization of oral bioavailability is of common interest because low bioavailability is often the cause of variable and poorly controlled clinical and toxic effects. This is of major importance for polar molecules such as peptides and proteins. " ... 

Meanwell NA, Krystal M (2007) Respiratory syncytial virus - the discovery and optimization of orally bioavailable fusion inhibitors. Drugs Future 32 441-455... 

Insolubility of drugs is a great obstacle for drug function in clinical remedy and solubilization has been an important technology for solving this problem in biomedical science. A solubilized oral formulation could enhance the oral bioavailability of insoluble drugs and is an optimal choice for patients who can not take capsules or tablets. 

Unity resulted in 4234 hits. After application of several filters and clustering of the remaining 1975 molecules, compounds from 18 of the 27 clusters were screened in Xenopus oocytes. One compound with an IC50 of 5.6pM belonged to a new class of Kvl.5 blockers and exhibited a favorable pharmacokinetic profile. After further optimization, compound 73 (IC50 = 0.7pM Fig. 16.9) resulted, with good oral bioavailability in rats [145]. 

This type of information about a homologous series of drug candidates, when considered in light of the propensity of these compounds to undergo first-pass metabolism and/or liver clearance, allows pharmaceutical scientists to make more intelligent decisions about which compounds to move into animal studies. In addition, when an in vitro-in vivo correlation can be demonstrated for a series of compounds, the results of Caco-2 experiments can be used as a guide by medicinal chemists to make structural modifications to optimize oral bioavailability. 

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