These results point to a central role of inflammation in the pathogenesis of UP in HD patients.

Proton pump inhibitors are a class of drugs which are widely prescribed for acid-related diseases. They are primarily metabolized by CYP2C19 and CYP3A4. It is unknown so far whether proton pump inhibitors are also substrates of the ATP-dependent efflux transporter P-glycoprotein. Moreover, it is not established whether proton pump inhibitors are also inhibitors of P-glycoprotein function. The aim of our study was therefore to characterize omeprazole, lansoprazole and pantoprazole as P-glycoprotein substrates and inhibitors. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells. Inhibition of P-glycoprotein-mediated transport was determined using the cyclosporine analogue PSC-833 (valspodar) as P-glycoprotein inhibitor. Inhibition of efflux transport by omeprazole, lansoprazole and pantoprazole was assessed using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, basal-to-apical transport of omeprazole, lansoprazole and pantoprazole was greater than apical-to-basal transport in Caco-2 and L-MDRI cells. Addition of PSC-833 (1 microM) showed a clear effect only for lansoprazole, suggesting that other transporters contribute to omeprazole and pantoprazole cellular translocation. Furthermore, all of the tested compounds inhibited digoxin transport with IC50 values of 17.7, 17.9 and 62.8 microM for omeprazole, pantoprazole and lansoprazole, respectively. In summary, our data provide evidence that proton pump inhibitors are substrates and inhibitors of P-glycoprotein. These findings might explain some of the drug interactions with proton pump inhibitors observed in vivo.

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Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

Accumulation of M3G and M6G is due to the substantially lowered clearance by residual renal function and peritoneal dialysis. In view of the accumulation of potential active metabolites, subsequent investigations have to assess the frequency of side-effects in patients on CAPD.

Background: A new neutral peritoneal dialysis fluid (PDF; Balance^®) provided in a two-compartment bag (pH 7.4, no plasticizers, minimal glucose degradation products – GDP) was investigated in comparison with a neutral control (Hanks’ balanced salt solution with gelatin 0.1%) and other PDFs with standard properties and plasticizers (Andy plus^®, pH 5.2, GDP), plasticizer free (stay safe^®, pH 5.2, GDP), and in addition plasticizer free after sterile filtration instead of heat sterilization (pH 5.2) regarding the function of peripheral blood leukocytes. Methods: Blood was drawn from 12 volunteers, and blood monocytes (MN) and polymorphonuclear leukocytes (PMNL) were collected. The cells were incubated for 30 min in control medium and the PDFs: glucose 1.5% (83 mmol/l) and 4.25% (238 mmol/l). Respiratory burst of cells was evaluated by chemiluminescence and superoxide (SO) generation after stimulation with phorbol myristate acetate. Results: In comparison with the control medium, incubation of MN in the two-compartment PDF showed preservation of respiratory burst. In contrast, the incubation of MN in standard PDF and plasticizer-free PDF showed impaired functions. The same was found for PMNL. SO anion measurement in MN and PMNL after incubation in the new two-compartment PDF also showed preservation of cell function in comparison with the control medium. The incubation of PMNL in standard PDF and plasticizer-free PDF with a high glucose content showed depressed SO anion generation. Conclusions: These in vitro data demonstrate a better preservation of in vitro phagocyte function with adaptation of pH and reduction of glucose, GDP, and plasticizers in PDFs. The best results are achieved with the two-compartment, lactate-based neutral PDF.

Objectives To evaluate the impact of a plasticizer-free device on exposure to di-(2-ethylhexyl) phthalate (DEHP) and its major metabolites in patients on continuous ambulatory peritoneal dialysis (CAPD). DEHP is the most commonly used plasticizer in polyvinyl chloride (PVC) products; it is added to CAPD bags in order to improve the flexibility of the material. Since DEHP leaches out of the plastic matrix, patients on CAPD are exposed to considerable amounts of DEHP and its metabolites. Design A prospective cross-over study. Setting Department of nephrology in a teaching hospital. Participants Six patients (4 female, 2 male) stable on peritoneal dialysis (PD) for at least 6 months. Interventions Patients were switched from a plasticizer-containing PVC CAPD system (A.N.D.Y. Plus, Fresenius Medical Care, Bad Homburg, Germany) to a polyolefine-made plasticizer-free system (stay-safe, Fresenius). Main Outcome Measures Prior to and 42 days after the switch, 24-hour effluent dialysate and urine collections were performed and 10 mL blood was drawn. Concentrations of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), phthalic acid (PA), and 2-ethylhexanol (2-EH) in urine, dialysate, and serum were determined using gas chromatography/mass spectrometry. Results Complete data were obtained from 5 patients. Serum levels of PA decreased significantly during the study period (0.137 ± 0.078 mg/L vs 0.124 ± 0.049 mg/L, p = 0.04), and the respective levels of DEHP decreased insignificantly (0.097 ± 0.076 mg/L vs 0.069 ± 0.046 mg/L, p = 0.07), whereas the concentrations of MEHP and 2-EH remained unchanged. Urine concentrations of PA were high (0.81 ± 0.69 mg/L) but did not change substantially (0.70 ± 0.50 mg/L). Effluent dialysate concentrations of MEHP and PA decreased significantly (0.0176 ± 0.004 mg/L vs 0.0040 ± 0.0007 mg/L, p = 0.043 and 0.158 ± 0.056 mg/L vs 0.111 ± 0.051 mg/L, p = 0.043, respectively). Conclusions Although PD patients seem to be exposed to other sources of phthalates in addition to dialysis, use of plasticizer-free devices may help to reduce potentially immunosuppressive exposure to phthalate esters.