Peptides pharmacokinetic studies

A careful comparative pharmacokinetic study of the tripeptoid 6.108 and the tetrapeptide N-phenylacetyl-Leu-Asp-Phe-D-Pro-amide (6.109) in rats has provided insights on absorption and disposition [233]. The two compounds have comparable backbone structures but differ in the presence or absence of peptide bonds. They also have similar octanol/water partition coefficients, although the H-bonding capacity of the tetrapeptide is greater. In an in vitro model, the two compounds had comparable, and low, absorption clearances (6.7 x 10 4 vs. 4.8 x 10 4 ml min-1 cnT1 for the peptoid and the... 

Yang, J.Z.,W. Chen, and R.T. Borchardt. 2002. In vitro stability and in vivo pharmacokinetic studies of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs. 

H. Heimecke, R. Woessner, F. Bitsch, Biological and Pharmacokinetic Studies with P-Peptides , Chimia 1998,52,734 - 739. 

Figure 9.12 The effective permeability (Pefr, mean T SD) of enalapril andenalaprilatein human jejunum in iwo.ThePeflrvalues predict the fraction dose absorbed for both drugs obtained in pharmacokinetic studies in humans. The higher jejunal Peff °f enalapril is most likely due to significantly higher transport through the peptide carrier.

Of the thymic hormones currently undergoing clinical evaluation, the most detailed pharmacokinetic studies have been performed with TF5 and Tuj. The parenteral administration of TF5 has been associated with the generation of detectable serum thymic hormone bioactivity as detected in the Bach-Dardenne assay (Iwata et ah, 1981). A 10-year-old child with chronic mucocutaneous candidiasis treated with TF5 showed a prompt rise of serum FTS-like bioactivity that persisted within the normal range for several weeks following the discontinuation of treatment, but which eventually returned to low levels (Iwata et ah, 1981). These studies have clearly demonstrated that the parenteral administration of TF5 generates detectable serum bioactivity. However, it cannot be determined which of the peptides present in TF5 gave rise to the serum activity. 

Because of some of the problems with bioassays and immunoassays, liquid chromatography (LC)-based techniques are increasingly applied as an alternative. While modern LC-based assays have a comparable sensitivity to immunoassays, they oftentimes are characterized by a higher selectivity [18, 19]. Muller et ah, for example, used LC/mass spectrometry with matrix-assisted laser desorption ionization in ex vivo pharmacokinetic studies in combination with enzyme inhibition experiments to investigate the complex metabolism of dynorphin Al-13, a peptide with opioid activity, up to the fifth metabolite generation [20, 21]. 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

Kristensen E. In vitro and in vivo studies on pharmacokinetics and metabolism of PNA constructs in rodents. In Peptide Nucleic Acids Methods and Protocols, Nielsen P. E. (Ed.). 2002, Humana Press (To-towa, N.J., United States) Copenhagen, pp. 259-269. 

Nanoparticle surface modification is of tremendous importance to prevent nanoparticle aggregation prior to injection, decrease the toxicity, and increase the solubility and the biocompatibility in a living system [20]. Imaging studies in mice clearly show that QD surface coatings alter the disposition and pharmacokinetic properties of the nanoparticles. The key factors in surface modifications include the use of proper solvents and chemicals or biomolecules used for the attachment of the drug, targeting ligands, proteins, peptides, nucleic acids etc. for their site-specific biomedical applications. The functionalized or capped nanoparticles should be preferably dispersible in aqueous media. 

Bioavailability and bioequivalence are also usually assessed in animals. Such studies are undertaken as part of pharmacokinetic and/or pharmacodynamic studies. Bioavailability relates to the proportion of a drug that actually reaches its site of action after administration. As most biopharmaceuticals are delivered parenterally (e.g. by injection), their bioavailability is virtually 100 per cent. On the other hand, administration of biopharmaceuticals by mouth would, in most instances, yield a bioavailability at or near 0 per cent. Bioavailability studies would be rendered more complex if, for example, a therapeutic peptide was being administered intranasally. 

Numerous studies have been published on the in vivo metabolism of peptides. However, these studies are concerned mainly with assessment of pharmacokinetic parameters such as half-life and clearance. Only seldom is the in vivo biotransformation of peptides that contain only common amino acids investigated in any detail, due to the difficulty of monitoring products of proteolysis that are identical to endogenous peptides and amino acids. More importantly, such studies fail to yield mechanistic and biochemical insights. For this reason, we begin here with a discussion of the metabolism of just a few peptides in some selected tissues, namely portals of entry (mouth, gastro-intestinal tract, nose, and skin), plasma, organs of elimination (liver, kidney), and pharmacodynamic sites (brain and cerebrospinal fluid). These examples serve as introduction for the presentation in Sect. 6.4.2 of the involvement of individual peptidases in peptide metabolism. 

The literature contains numerous references to the use of MS/MS in the determination of new neuropeptides in identified cells of invertebrates (Bulau et al., 2004, for a recent example) and this technique is now being applied to in situ analysis of vertebrate tissues (Fournier et al., 2003). MS/MS is also used for studies of neuropeptide processing (Nilsson et al., 2001), pharmacokinetics of synthetic peptides (Mock et al., 2002), nonpeptide drug metabolism (Kamel et al., 2003), identification of peptides purified by immunoaffinity (Suresh Babu et al., 2004), and MALDI/MS/MS techniques adaptable to brain dialysis (Bogan and Agnes, 2004). 

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