Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby enhancing drug discovery and providing a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution.

https://science.sciencemag.org/content/sci/286/5439/487.full.pdf

Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics

The condensation reaction between p-tert-butylphenol and formaldehyde leads in a single step to good yields of cyclic oligomers in which, depending on the reaction conditions, either four, six, or eight phenol units are joined by methylene bridges. The beakerlike shape of the most stable conformation of the tetramer has led to their being given the name “calixarenes” (calix = chalice). Resorcinol can undergo condensation in a similar manner with a variety of aldehydes to afford cyclic tetramers with the same basic structure (the resorcarenes). In both cases the reaction does not require the use of dilution techniques, so that large quantities of product can be readily obtained. In addition, the parent compounds can be modified in various ways, in particular at the phenolic hydroxy groups or the phenyl residues; these approaches can be used separately or in combination. Calixarenes are thus ideal starting materials for the synthesis of various types of host molecules and can also act as building blocks for the construction of larger molecular systems with defined structures and functions. Their potential applications range from use as highly specific ligands for analytical chemistry, sensor techniques and medical diagnostics to their use in the decontamination of waste water and the construction of artificial enzymes and the synthesis of new materials for non-linear optics or for ultrathin layers and sieve membranes with molecular pores.

Calixarenes, Macrocycles with (Almost) Unlimited Possibilities

https://www.ajkd.org/article/S0272-6386(12)80312-X/pdf

Tubulointerstitial changes as a major determinant in the progression of renal damage.

AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

Targeted delivery of low molecular drugs using chitosan and its derivatives.

https://www.kidney-international.org/article/S0085-2538(15)60344-1/pdf

Drug-targeting to the kidney: Renal delivery and degradation of a naproxen-lysozyme conjugate in vivo

Three new calixspherands (2-4) were synthesized in good yields (>60%) via a new method; p-tert-butylcalix[4]arene (6) is bridged with a m-terphenyl (7-9) and subsequently alkylated. H-1 NMR spectroscopy and X-ray crystallography showed that all the complexes are in a partial cone conformation. All the calixspherands form kinetically stable complexes with Na+, K+, and Rb+. The kinetic stability was determined both by H-1 NMR spectroscopy, in CDCl3 saturated with D2O, and by a new method based on the exchange of radioactive rubidium or sodium in the complexes for nonradioactive sodium in different solvents. Both methods showed that the kinetic stability of the different complexes is strongly increased when the size of the group on the central aromatic ring of the m-terphenyl is increased. This effect is most pronounced for the rubidium complexes. The half-life times for decomplexation, in CDCl3 saturated with D2O, increased from 2.8 h for [1.Rb]+ to 139 h and 180 days for [2.Rb]+ and [3.Rb]+, respectively. The ''exchange method'' shows that the rate of decomplexation is the rate-limiting step in the exchange of rubidium in the complex for sodium present in solution. These results can be explained in terms of increased shielding of the cavity from solvent molecules. The kinetic stabilities of the complex of 3 with Na+, K+, and Rb+ are the highest ever reported.

/pdf/kinetically-stable-complexes-of-alkali-cations-with-117uw957sq.pdf

Kinetically stable complexes of alkali cations with calixspherands : An evaluation of shielding

The mesangial cells of the glomerulus, the proximal tubular cells and the interstitial fibroblasts are the first choice targets for renal drug delivery since they play a pivotal role in many disease processes in the kidney. In the present review, only targeting to the proximal tubular cell is addressed because only this has been studied extensively. Two approaches of drug delivery to the proximal tubular cell have been studied up to now, the prodrug/softdrug and low-molecular-weight protein (LMPWP) approach. Most research on tubular specific drug delivery has focused on the development of amino-acid prodrugs that, after delivery, require activation by more or less kidney-selective enzymes. Large differences in renal selectivity are found. For some prodrugs, a rapid removal of the released drug from the kidney explained the low renal selectivity whereas for others, cleavage in non-target tissue and insufficient transport across the cell to the enzyme site seemed mainly responsible. The LMWP approach is based on drug attachment to a protein (<30 kD) that is freely filtered through the glomerulus and after accumulation is selectively catabolized in the lysosomes of the proximal tubular cell. Using LMWPs as drug carriers, a higher renal selectivity can be attained and a broader range of drugs can be attached while the rate of drug release can also be manipulated. The studies with captopril-lysozyme and naproxen-lysozyme clearly showed that targeting resulted in a higher renal selectivity and that drugs delivered into and regenerated in the proximal tubular cell exert renal selective pharmacological activity. Further testing will provide more definite data on the added value of this delivery technology.

Specific drug delivery to the kidney.

https://www.kidney-international.org/article/S0085-2538(15)58014-9/pdf

Quantification of renal low-molecular-weight protein handling in the intact rat.

/pdf/transport-mechanisms-for-cationic-drugs-and-proteins-in-2nfjtburxa.pdf

Transport mechanisms for cationic drugs and proteins in kidney, liver and intestine: implication for drug interactions and cell-specific drug delivery.

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