Pharmacokinetic modifiers

The pharmacokinetics of a radiopharmaceutical can be systematically altered by chemical modification of the targeting biomolecule or metal chelate, and the use of a pharmacokinetic modifying Hnker. The chemical modification of a biomolecule can be achieved by introducing various hydrophiUc or Hpophilic groups onto the side-chains of the targeting biomolecule. Sometimes a peptide sequence, such as polyaspartic acid, can be used to improve the hydrophiUcity. The chemical modification of the metal chelate can be achieved using BFCs with different charge and hydrophiUcity. 

Release of a pharmacokinetic modifier (causing enzymatic induction, displacing protein-bound molecules, altering drug excretion, etc.). 

Examples of pharmaceutically useful groups include hydrophUic-ity and hydrophobicity modifiers, pharmacokinetic modifiers, antigens, receptor ligands, nucleotides, chemotherapeutic agents, antibacterial agents, antiviral agents, immimomodulators, hormones and their analogs, enzymes, inhibitors, alkaloids, and therapeutic radionuclides. 

A linker is usually introduced between the imaging probe and the ligand, with the aim to preclude or rnitiitnize imwanted interferences between these two moieties. Linkers may act as a pharmacokinetic modifier and have a profound impact on the biodistribution of the whole molecule (Rufini, 2006 Schottelius, 2004). The most popular linkers are short amino... 

The receptor represents the locus of dmg action. However, the pharmacokinetic processes of absorption (dmg entry), distribution, metaboHsm, and excretion play principal roles in determining in vivo time courses and concentrations of dmgs and thus modify actions initiated at receptors. 

Smith CM, Wang X, Hu H, et al. 1995. A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect 103 248-253. 

A clear priority remains to expand the panel of intestinal efflux transporters that are expressed individually in modified cell lines. These research tools will be instrumental in identifying and validating selective probe transporter substrates and inhibitors. The availability of such probes will allow for a better understanding of the influence of transporters on in vivo pharmacokinetics. A similar set of probes has been instrumental in increasing our understanding of the role that cytochrome P450 plays in human pharmacokinetics and in avoiding issues associated with these enzymes. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Gotteries, J., Svenheden, A., Alpsten, M., Bake, B., Larsson, A. et al., Gastrointestinal transit of amoxicillin modified-release tablets and a placebo tablet including pharmacokinetic assessments of amoxicillin, Scand. J. Gastroenterol. 1996, 32, 49-53. 

Poduslo JF, Curran GL, Gill JS. Pu-trescine-modified nerve growth factor bioactivity, plasma pharmacokinetics, blood-brain/nerve barrier permeability and nervous system biodistribution. 

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