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Pharmacokinetic-Pharmacodynamic Modeling of Irreversible Drug Effects
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
In other cases, antimicrobial delivery into less accessible sites is required. These include penetration into the cerebrospinal fluid, eye, and prostate gland. In addition, penetration of some antimicrobials into intracellular sites is important in treating pathogens that multiply within mammalian cells. All of these sites demonstrate a lipophilic barrier which restricts passive diffusion of many drugs.12 Therefore, drugs that are more lipophilic are more likely to be able to enter these restricted sites by diffusion across this lipid barrier. Paradoxically, many of these same drugs are highly bound to serum albumin. Another mechanism by which drugs may enter intracellular fluid is through ion “trapping”.12 The quinolones are a good example of this. At physiologic pH, the quinolones are unionized and more lipid soluble. Once they enter the more acid intracellular fluid, they become ionized and are less able to diffuse out of cells.
Therapeutic Monitoring of Adverse Drug Reactions (ADRs)
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Alkalinization or acidification of urine, although based on valid chemical pharmacokinetic principles of ion trapping and acid–base reactions, is not clinically recommended. Practically, the concept is not effective, and it may aggravate or complicate the removal of agents that interfere with acid–base balance.
Clinical pharmacology and therapeutics: nonopioids
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
A number of factors may explain nabumetone’s safety profile. Unlike other non-specific NSAIDs, but like all COX-2 inhibitors apart from lumiracoxib, it is a non-acidic drug. This may diminish any topical effect or ion trapping. It is a prodrug, undergoing extensive first pass metabolism to the active 6-methoxy, 2-naphtylactic acid (6-MNA), which does not undergo enterohepatic circulation, fitting well with the topical theory. Finally, nabumetone is somewhat COX-2 selective.
Pharmacokinetics of antibiotics for pleural infection
Published in Expert Review of Respiratory Medicine, 2022
Estee P M Lau, Calvinjit Sidhu, Natalia D Popowicz, Y. C. Gary Lee
When the antibiotic eventually reaches the pleural fluid, its pharmacokinetics can be further influenced by a low pleural fluid pH (a characteristic of pleural infection), altering the pharmacokinetic profile of pH sensitive antibiotics [34]. For instance, azithromycin has a second basic ionizable group that makes it more likely to be ionized in an acidic environment leading to ‘ion trapping’ in the pleural space [35]. Indeed, Saroglou et al [36] found that the half-life (t½) of azithromycin was twice as long in the pleural empyema fluid when compared to serum. Moreover, high protein concentrations found in exudative parapneumonic effusions can ‘trap’ antibiotics with a high protein binding affinity, leading to a prolonged exposure of the antibiotic at the target site. This was confirmed by Benoni et al [37], who found that the t½ of ceftriaxone, a highly protein bound antibiotic, was two to four times longer in pleural fluid containing high protein content when compared to serum.
Liposome supported peritoneal dialysis in rat amitriptyline exposure with and without intravenous lipid emulsion
Published in Journal of Liposome Research, 2019
Robin Chapman, Martyn Harvey, Paul Davies, Zimei Wu, Grant Cave
Liposome supported peritoneal dialysis (LSPD) is a newly described technique with the potential to augment clearance of xenobiotic once absorbed that is not able to be cleared by hemodialysis (Forster et al.2014). Liposomes are nano- to micrometer sized spherical structures of lipid bilayer, constituent molecules having amphiphilic outer poles that enable suspension in water based solutions. The lipid bilayer encloses a water droplet, the water soluble components of which are able to be manipulated. pH manipulation to make the aqueous core acidic enables ion trapping of lipophilic weak bases (such as amitriptyline) in the liposomal core. At physiologic pH amitriptyline is unionized and can freely pass through the lipid rich liposome membrane. In the presence of an acidic central pH amitriptyline ionizes, becoming hydrophilic and thus is trapped within the liposome core (Forster et al.2012). This ion trapping process has been seen in liposomes traditionally loaded in vitro and the resulting suspensions are used as sustained release drug preparations (Putz et al.2010). Current research is investigating changing the site of drug loading to in vivo, thus ameliorating drug toxicity (Cave et al.in press).
Estrogen-functionalized liposomes grafted with glutathione-responsive sheddable chotooligosaccharides for the therapy of osteosarcoma
Published in Drug Delivery, 2018
Xuelei Yin, Shuaishuai Feng, Yingying Chi, Jinhu Liu, Kaoxiang Sun, Chuanyou Guo, Zimei Wu
It is worth of mentioning that Chol-SS-COS/ES produced strongest fluorescence intensity in the MG63 cells than the free DOX following exposure to cells for up to 4 h (Figure 4). As only the non-ionized form of DOX (basic pKa of 8.3) distributes on both sides of the cell membrane, ionized DOX is sequestered in the extracellular environment (in tumor pH could be 6.5) or organelles with low pH such as endosomal and lysosomes (‘Ion Trapping’ phenomenon) (Wojtkowiak et al., 2011). This may result in drug resistance. Therefore, intracellularly delivery with liposomes can be efficient to overcome the ‘Ion Trapping’ phenomenon, if DL is sufficient (Xu et al., 2014). These results confirmed the role of estrogen-receptor-mediated endocytosis in efficient intracellular delivery of the DOX via estrogen receptor-targeted liposomes. In addition, the formulations showed larger discrepancy in cellular uptake than in the cytotoxicity study. This is more likely due to the fact the in vitro cytotoxicity study was carried out following longer time of drug exposure (24 h) to the cells in which case all liposomes.