Amino acid bioavailability

However, since the PER is an in vivo test, protein digestibility and amino acid bioavailability are encompassed to some extent within the assay. Despite these advantages, it is difficult to determine the individual contribution of digestibility and bioavailability of individual amino acids, or of individual proteins in a complex mixture, on overall protein quality. There are indications that the assay can be shortened from 4 weeks to 2 weeks with little loss in accuracy (Hackler, 1977). 

The advantages of an animal bioassay are that protein digestibility, amino acid bioavailability, and the presence of antinutritional factors can be ascertained. However, animal-based feeding studies can be difficult. First, these assays are expensive to conduct and time-consuming. Secondly, these assays require animals... 

Robbins, K. R. and Ballew, J. E. (1982). Effect of alkaline treatment of soy protein on sulfur amino acid bioavailability. J. Food Sci. 47, 2070-2071. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

However, most natural peptides are composed of L-form a-amino acids and because of the ubiquitous prevalence of peptidases they have limited biostability, and consequently low bioavailability. Thus, a novel field of peptidomimetics has emerged in drug discovery, in attempts to design non-peptide compounds mimicking the pharmacophore and thus the activity of the original peptide. 

A number of other peptide molecules are currently being explored for delivery via inhalation (6). Very recently, a much smaller peptide (leuprolide, about 9 amino acid residues) has been delivered by metered dose inhaler (MDI) in a characterized fashion to humans (7). This work revealed that about 50% of a dose deposited in the lung could be bioavailable. This value is much greater than those reported for nasal bioavailabilities of this and similar molecules (8). These results, and ours in the rat lung (9), imply that inhalation administration of some peptide and polypeptide molecules is perfectly feasible. 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

The pivotal role of natural a-amino acids among a myriad of biologically active molecules is widely appreciated, and is of particular importance in the pharmaceutical industry. Unnatural a-amino acids also have a prominent position in the development of new pharmaceutical products. It has been shown that substitution of natural a-amino acids for unnatural amino acids can often impart significant improvements in physical, chemical and biological properties such as resistance to proteolytic breakdown, stability, bioavailability, and efficacy. One of the many synthetic methods available for the production of enantiomerically enriched a-amino acids is the metal-catalyzed enantioselective reduction of a-de-hydroamino acid derivatives [90]. 

Acid-forming amino acids, effect on Ca bioavailability, 76... 

Further efforts in related series afforded structurally similar DPP-4 inhibitors such as acid 13 (E. Parmee, unpublished results), thiazole 14 [35] and cyclopentylglycine 15 (Figure 17.3) [36], Although 15 did not show improved selectivity over DPP-8/9,13 and 14 showed some improvement in selectivity over these counterscreens. Nevertheless, none of these compounds exhibited sufficient selectivity to merit further pursuit zwitterion 13 also possesses low oral bioavailability in rats (F < 1%). Consequently, focus in the a-amino acid series shifted to acyclic derivatives. 

Incorporation of the P-amino acid amide from 25 into piperazine hit 26 improved DPP-4 inhibition by more than 80-fold and led to the discovery of 32 (Table 17.5) [46], The 2-fluorophenyl effect on DPP-4 potency was again observed with compound 33 however, this compound showed very high clearance and no oral bioavailability in the rat. More simplified truncated compounds 34 and 35 showed decreased DPP-4 potency by 10-fold compared to 33, and the removal of the benzyl group resulted in a more significant loss of DPP-4 activity (36). Unfortunately, while 34 showed good... 

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