Pharmacokinetic behavior

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987 Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of... 

Sato A, Endoh K, Kaneko T, et al. 1991. A simulation study of physiological factors affecting pharmacokinetic behavior of organic solvent vapours. Br J Ind Med 48 342-347. 

CE was early identified as a powerful experimental technique to monitor the partitioning of neutral solutes and the neutral form of ionizable compounds [67]. In the search of partitioning parameters closer than log Poa to the pharmacokinetic behavior of dmg compounds [68] several different CE experimental conditions were explored and recently reviewed in detail [5, 69]. 

Testa, B., Crivori, P., Reist, M., Carrupt, P. A. The influence of lipophilicity on the pharmacokinetic behavior of drugs concepts and examples. Perspect. Drug Discov. Des. 2000, 79,179-211. 

A Garzon, A Poupaert, M Claesen, P Dumont. A lymphotropic prodrug of L-dopa Synthesis, pharmacological properties, and pharmacokinetic behavior of 1,3-dihex-adecanoyl-2-r(S)-2-amino-3-(3,4-dihydroxyphenyl) propanoyl] propane-1,2,3-triol. J Med Chem 29 687-691, 1986. 

It is only during the past few years that the importance of the metabolic and pharmacokinetic behavior of drug molecules in the drug discovery process has been recognized. One of the causes for failure in drug development is the lack of suitable pharmacokinetic properties of drug candidates. At the same time, the development... 

It has become increasingly accepted that the pharmacokinetic behavior of new drugs represents an important attribute, along with efficacy and safety. The frequency with which a drug must be taken is a function of several factors the half-life, the span between minimally efficacious concentrations and concentrations that cause side-effects, and the pharmacokinetic-pharmacodynamic relationship. Typically medicinal chemists optimize the predicted pharmacokinetics of... 

Finally, work that may facilitate understanding the role of oq-acid glycoprotein variants in inter-individual variations in plasma protein binding, pharmacokinetic behavior, and drug action has been described. A capillary zone electrophoresis method that allows for the determination of 11 intact forms (i.e., isoforms, glycoforms) of oq-acid glycoprotein has been described [84],... 

The data sets in Tables VII, VIII, and IX are divided into different categories in terms of reactivity of the two metal centers and pharmacokinetic behavior, while the data points included in Fig. 21 are chronologically indicated by the abbreviations shown below. 

During preclinical assessment of an enantiometric mixture, it may be important to determine to which of these three classes it belongs. The pharmacological and toxicological properties of the individual isomers should be characterized. The pharmacokinetic profile of each isomer should be characterized in animal models with regard to disposition and interconversion. It is not at all unusual for each enantiomer to have a completely different pharmacokinetic behavior. 

Stereoisomerism will influence metabolism and toxicity. For example, Lu et al. (1998) reported a comparison of (5)-(—jlfosfamide and (i )-(+)-Ifsosfamide. They demonstrated that there were significant differences between the two stereoisomers with regard to pharmacokinetic behavior and major metabolite formation, as shown in Table 18.13. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

It appears that qualitative correlations between antibacterial activity and rate constants of HO ion catalyzed hydrolysis are fortuitous since many factors other than transpeptidase acylation contribute to antimicrobial activity. These other contributing factors include permeation of the outer membrane of the bacterial cell wall, resistance to /3-lactamase, the fit in the active site of the enzyme, stability of the acylated enzyme, and, last but not least, in vivo pharmacokinetic behavior. 

A number of clinically useful drugs have been derivatized with a peptide pro-moiety with the view to improve pharmaceutical properties (e.g., solubility) and/or pharmacokinetic behavior (e.g., absorption or targeted delivery). In such cases, and in contrast to the peptides and derivatives and analogues discussed in Sect. 6.3- 6.6, the peptide unit is not part of the pharmacophore. 

A first and apparently straightforward strategy to improve pharmacokinetic behavior of bioactive peptides is to derivatize the N-terminus, the C-terminus, and/or one or more functionalized side chains. Different biological consequences are conceivable depending on the stability and intrinsic activity of the derivative. 

A major and relevant difference between the two compounds was their in vivo biotransformation. Whereas the peptoid was metabolically stable (>90% excreted unchanged after i.v. administration), the peptide was extensively metabolized (ca. 2% excreted unchanged after i.v. administration). In conclusion, metabolic stability was achieved with the tripeptoid 6.108, but its pharmacokinetic behavior was clearly unsatisfactory due to poor oral absorption and fast biliary excretion. 

In summary, (oxodioxolyl)methyl esters of carboxylic acid drugs appear to be generally useful as prodrugs. However, more studies are needed to document the structure-metabolism relationships, the relative contribution of enzymatic vs. nonenzymatic reactions in their in vivo activation, the reasons of some failures, their toxic potential, and their pharmacokinetic behavior in humans. 

Another type of reaction was seen for dalvastatin (8.151), a prodrug that bears an unsaturated side chain. The hydrolysis of dalvastatin to the active acid competes with epimerization at C(6), the rate of the reaction being independent of pH above pH 2 [192], The mechanism is believed to be one of heterolytic cleavage of the C(6)-0 bond to generate a C-centered carbonium ion stabilized by the extended conjugated system characteristic of this compound. In the pH range 2 - 7, the rate of epimerization was found to be ca. 100 times faster than hydrolysis. Above pH 7, base catalysis accelerates hydrolysis, the rate of which increases ca. 100-fold between pH 7 and 9. These facts serve only to complicate the design of HMG-CoA reductase inhibitors and the interpretation of their pharmacokinetic behavior. 

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