Intracellular drug

Upadhyay KK, Bhatt AN, Mishra AK, Dwarakanath BS, Jain S, Schatz C, Le Meins JE, Earooque A, Chandraiah G, Jain AK, Misra A, Lecommandoux S (2010) The intracellular drug delivery and anti tumor activity of doxorubicin loaded poly(y-benzyl L-glutamate)-b-hyaluronan polymersomes. Biomaterials 31(10) 2882... 

Synthetic Polymers. Synthetic polymers are versatile and offer promise for both targeting and extracellular-intracellular drug delivery. Of the many soluble synthetic polymers known, the poly(amino acids) [poly(L-lysine), poly(L-aspartic acid), and poly(glutamic acid)], poly(hydroxypropylmethacrylamide) copolymers (polyHPMA), and maleic anhydride copolymers have been investigated extensively, particularly in the treatment of cancers. A brief discussion of these materials is presented. 

Meyer O, et al. Cationic liposomes coated with polyethylene glycol as carriers for oligonucleotides. J Biol Chem 1998 273 15621 Shi G, et al. Efficient intracellular drug and gene delivery using folate receptor-targeted pH-sensitive liposomes composed of cationic/anionic lipid combinations. J Control Release 2002 80 309. 

Torchilin VP, Levchenko TS. TAT-liposomes a novel intracellular drug carrier. Curr Protein Pept Sci 2003 4(2) 133-140. 

The major mechanism of resistance that has been identified for paclitaxel is transport out of tumor cells, which leads to decreased intracellular drug accumulation. This form of resistance is mediated by the multidrug transporter P-glycoprotein. 

A121a cells were exposed to paclitaxel at concentrations of 0.2, 0.8, 2, and 5 ng/mL. Paclitaxel uptake by cells was able to be quantified at each time point under four treatment conditions. The lowest measured intracellular accumulation was 6.5 pg/106 cells, observed 10 min after the addition of 0.2 ng/mL paclitaxel to cells. The detected concentration in this sample corresponded to approximately 9.6 pg/mL drug in the cell lysate, which is nearly twice the LOQ. Foremost concentrations of paclitaxel, it appeared that the intracellular drug concentrations increased rapidly with exposure time and reached a plateau within 1-3 h. However, for cells exposed to the lowest concentration (0.2 ng/mL), the maximum intracellular drug concentration apparently was not achieved within 6 h, which was longest time interval investigated. In future studies, these data will be expanded to include additional concentrations and exposure times, and analyzed according to cellular pharmacokinetic models such as those published previously [12],... 

Drug Cell type Intracellular drug (ng/106 cells)... 

Second, certain nucleotide phosphonates (e.g., adefovir and cidofovir) are effective antivirals, but their use in the clinic is limited by renal toxicity. This is believed to be caused by avid uptake at the basolateral membrane of renal proximal tubule cells followed by slow transport into the urine at the apical membrane, a sequence of events that results in intracellular drug accumulation and thus toxicity. As with penicillin, the OAT family of transporters has been implicated in cidofovir uptake. Co-administration of probenecid with cidofovir has been shown to decrease renal clearance of the antiviral and reduce its nephrotoxicity, presumably through com-... 

Both a short-term intracellular drug accumulation and a long-term viability assay have been used to understand the anticancer properties of the effects of flavonoids against tumor cells [14,16]. 

An interesting exception to the absolute validity of the tifth postulate is the considerable activity of chloramphenicol derivatives in cell-free model systems of protein synthesis when these derivatives are substituted with amino acyl residues instead of with dichloroacetyl as is the antibiotic itself (rev. in 2°)). This has been traced to the necessity of the dichloroacetyl grouping in aiding in the permeation of the antibiotic through the bacterial envelope 21 The amino acyl derivatives have very low antibacterial activity 20. Permeation failures of actinomycin D, macrolides and distamycin A with respect to certain families of bacteria occlude the action of these antibiotics on their intracellular drug receptors and target reactions but can be overcome experimentally by measures which render test organisms permeable. 

Dixon, K. H., Horton, J., Kelley, K., Morrow, C., Cowan, K. H. (1992). Reduced intracellular drug accumulation in the absence of P-glycoprotein (mdrl) overexpression in mitoxantrone-resistant human MCF-7 breast cancer cells. Cancer Res. 52, 6175-6181. 

Decreased uptake leads to lower intracellular drug concentrations. In many cisplatin-resistant cell lines, reduced accumulation was observed. The cisplatin membrane transport system is poorly understood, but studies on cisplatin-resistant cells with decreased drug accumulation have identified two membrane proteins that may be involved in uptake and efflux respectively a 48-kDa protein with decreased expression and a 200-kDa glycoprotein with increased expression. 

Luminal and Membrane Metabolism of Peptides and Proteins. In meaningful studies on peptide and protein drug absorption in the small intestine, it is prerequisite to distinguish among cavital, membrane contact, and intracellular drug metabolism.Cavital metabolism takes place in the lumen of the small intestine by enzymes such as trypsin, chymotrypsin, carboxypepti-dase, and elastase, which are secreted by the pancreas. Membrane contact metabolism is carried out by aminopeptidases lo-calized on the brush border membrane. Intracellular metabolism occurs inside of the cells. The known intra-celluar enzymes are cytoplasmic peptidases, prolidase, dipeptidase, and tripeptidase.A more detailed dis-cussion of this topic is presented in section Intestinal Absorption Barriers, later. 

In eight patients a single 500 mg oral dose of azithromycin was not substantially removed by continuous ambulatory peritoneal dialysis in the absence of peritonitis. Azithromycin cannot be recommended for widespread use in CAPD at present. However, the successful use of azithromycin in treating peritonitis, perhaps because of an intracellular drug transport mechanism, has been reported (44). 

Resistance involves reduced intracellular drug activation and is rare among usually susceptible bacteria. There is one report of metronidazole-resistant isolates of B. fragilis from a horse with pleuropneumonia. 

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