Transporters are important determinants of drug absorption, distribution, and excretion. The clinical relevance of drug transporters in drug disposition and toxicology depends on their localization in liver, kidney, and brain. There has been growing evidence regarding the importance of disease status on alterations in metabolizing enzymes and transporter proteins. This review focuses on uptake and efflux transporter proteins in liver, kidney, and brain and discusses mechanisms of altered transporter expression and function secondary to disease.
Background: Rituximab (RTX) is a chimeric monoclonal anti-CD20 antibody used off-label in the treatment of membranous nephropathy (MN). Unfortunately, limited information is available on the pharmacokinetics of therapeutic proteins such as RTX in patients with glomerular kidney diseases. Objective: The current study evaluated RTX pharmacokinetics in patients with MN (n=20) who received 4 RTX weekly intravenous infusions (375 mg/m 2) over a month, with a repeat of the identical treatment at 6 months. Baseline patient characteristics were gender (17M/3F), age (49±13 years), and body surface area (2.2±0.24 m 2). Methods: Compartmental pharmacokinetic analyses were conducted using Phoenix® and comparisons of these parameters were made between the MN patients and published data from two reference populations without kidney diseases (follicular lymphoma and autoimmune disorders). Results: Patients with MN exhibited a shorter half-life, reduced volume of central compartment, decreased area under the serum concentration-time curve (exposure), and increased RTX clearance from central compartment vs. previous reports in the reference patient populations. Conclusions and Relevance: These results suggest that shorter half-life and lower exposures to RTX in patients with MN may necessitate higher doses and/or changes to dosing frequency in order to optimize the relationships between serum concentrations and therapeutic effects.
Misfolded protein aggregation, including cataract, cause a significant amount of blindness worldwide. α-Crystallin is reported to bind misfolded proteins and prevent their aggregation. We hypothesize that supplementing retina and lens with α-crystallin may help to delay disease onset. The purpose of this study was to determine if αB-crystallin subunits containing a cell penetration peptide (gC-tagged αB-crystallin) facilitate the uptake of wild type αA-crystallin (WT-αA) in lens and retina. Recombinant human αB-crystallin was modified by the addition of a novel cell penetration peptide derived from the gC gene product of herpes simplex virus (gC-αB). Recombinant gC-αB and wild-type αA-crystallin (WT-αA) were purified from E. coli over-expression cultures. After Alexa-labeling of WT-αA, these proteins were mixed at ratios of 1:2, 1:5 and 1:10, respectively, and incubated at 37°C for 4 hours to allow for subunit exchange. Mixed oligomers were subsequently incubated with tissue culture cells or mouse organ cultures. Similarly, crystallin mixtures were injected into the vitreous of rat eyes. At various times after exposure, tissues were harvested and analyzed for protein uptake by confocal microscopy or flow cytometry. Chaperone-like activity assays were performed on α-crystallins ratios showing optimal uptake using chemically-induced or heat induced substrate aggregation assays. As determined by flow cytometry, a ratio of 1:5 for gC-αB to WT-αA was found to be optimal for uptake into retinal pigmented epithelial cells (ARPE-19). Chaperone-like activity assays demonstrated that hetero-oligomeric complex of gC-αB to WT-αA (in 1:5 ratio) retained protein aggregation protection. We observed a significant increase in protein uptake when optimized (gC-αB to WT-αA (1:5 ratio)) hetero-oligomers were used in mouse lens and retinal organ cultures. Increased levels of α-crystallin were found in lens and retina following intravitreal injection of homo- and hetero-oligomers in rats.
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