Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8 kg/m2 with an excess body weight loss of 54.9%. The AUC24 of all drugs were increased after laparoscopic sleeve gastrectomy by 46%, 55%, 77%, and 74%, respectively. The maximum concentrations were increased for tacrolimus, extended-release tacrolimus, and mycophenolate mofetil by 43%, 46%, and 65%. The apparent total clearances were decreased for tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium by 36%, 57%, and 38%. Laparoscopic sleeve gastrectomy can be associated with significant changes in pharmacokinetics of the drugs evaluated. The mechanism is likely decreased apparent drug clearance due to an increased drug exposure (from a more distal site of intestinal absorption with decreased intestinal metabolism), or decreased clearance (liver metabolism). Adapting the monitoring of immunosuppression will be important to avoid overdosing and potential side effects.

Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30-50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.

Chronic renal failure (CRF) leads to decreased drug renal clearance due to a reduction in the glomerular filtration rate. However, little is known about how renal failure affects renal metabolism and elimination of drugs. Because both depend on the activity of uptake and efflux by renal transporters as well as enzymes in tubular cells, the purpose of this study was to investigate the effects of CRF on the expression and activity of select renal drug transporters and cytochrome P450. Two groups of rats were studied: control and CRF (induced by 5/6 nephrectomy). Compared with control rats, we observed reductions in the expression of both protein and mRNA of Cyp1a, sodium-dependent phosphate transport protein 1, organic anion transporter (Oat)1, 2, and 3, OatK1/K2, organic anion-transporting polypeptide (Oatp)1 and 4c1, P-glycoprotein, and urate transporter 1, whereas an induction in the protein and mRNA expression of Mrp2, 3, and 4 and Oatp2 and 3 was observed. Cyp3a expression remained unchanged. Similar results were obtained by incubating a human proximal tubule cell line (human kidney-2) with sera from CRF rats, suggesting the presence of uremic modulators. Finally, the renal elimination of [(3)H]digoxin and [(14)C]benzylpenicillin was decreased in CRF rats, compared with controls, as shown by a 4- and 9-fold accumulation, respectively, of these drugs in kidneys of rats in CRF. Our results demonstrate that CRF affects the expression and activity of several kidney drug transporters leading to the intrarenal accumulation of drugs and reduced renal clearance that could, at least partially, explain the tubular toxicity of many drugs.

ESR Endangered Species Research Contact the journal Facebook Twitter RSS Mailing List Subscribe to our mailing list via Mailchimp HomeLatest VolumeAbout the JournalEditorsSpecials ESR 15:179-194 (2011) - DOI: https://doi.org/10.3354/esr00370 Spatial variation in right whale food, Calanus finmarchicus, in the Bay of Fundy Josée Michaud1,2,*, Christopher T. Taggart1 1Department of Oceanography, Dalhousie University, 1355 Oxford Street, Halifax, Nova Scotia B3H 4J1 Canada 2Present address: Pavillon Alexandre-Vachon, Room 4081, 1045, avenue de la Médecine, Université Laval, Québec, Québec G1V 0A6, Canada *Email: josee.michaud@arcticnet.ulaval.ca ABSTRACT: We quantified small- and basin-scale variation in the energy available in right whale (Eubalaena glacialis) food, Calanus finmarchicus Copepodite-5 (C5), as a function of depth, tidal variation and circulation during the late-summer feeding period in the Grand Manan Basin of the Bay of Fundy. Food energy density (kJ m−3) is a function of C5 concentration (m−3) and individual C5 lipid energy content (J) that increases by 2 orders of magnitude from near the surface to ~18 kJ m−3 at ~160 m depth; this observation helps explain why right whales concentrate their foraging efforts at depth. Food energy density can vary by a factor of 4 over a tidal cycle and 3.5 over a horizontal distance of ~2 km in the deeper strata of the Basin. By tracing water mass trajectories, we show that it is the warmer, saltier and denser water that contains the highest food energy density that is tidally advected within the Basin. At the scale of the Basin (10s of kilometres) we observed maximum food energy densities of ~25 kJ m−3 in the 140 to 160 m depth stratum where the highest energy densities spatially coincide with the highest historical right whale concentrations. We concluded that the tidal variation and tidally driven circulation represents the simplest explanation for the distribution of food energy density and for the distribution of right whales in the Grand Manan Basin region and that Basin topography and water mass excursions associated with tidal currents facilitate the persistence of C5 aggregations in the dense deep water. KEY WORDS: Right whale · Calanus finmarchicus · Energy content · Tide · Bay of Fundy Full text in pdf format Supplementary material NextCite this article as: Michaud J, Taggart CT (2011) Spatial variation in right whale food, Calanus finmarchicus, in the Bay of Fundy. Endang Species Res 15:179-194. https://doi.org/10.3354/esr00370 Export citation RSS - Facebook - Tweet - linkedIn Cited by Published in ESR Vol. 15, No. 3. Online publication date: November 30, 2011 Print ISSN: 1863-5407; Online ISSN: 1613-4796 Copyright © 2011 Inter-Research.

Drug metabolism could be altered in patients with chronic renal failure (CRF). In rats, this phenomenon is related to a decrease in liver cytochrome P450 (P450) and phase II enzymes, particularly N-acetyltransferase 2 (NAT2). This study attempted to determine the effects of CRF on liver P450 isoforms and NAT2 expressions by using a CRF mouse model. Two groups of mice were studied: CRF induced by 3/4 nephrectomy and control. Liver protein expression and mRNA levels of the major P450 isoforms involved in drug metabolism (CYP1A2, 2C29, 2D, 2E1, and 3A11) and NAT2 were measured by Western blot and real-time polymerase chain reaction (PCR), respectively. CYP3A activity was also assessed by the N-demethylation of erythromycin. Results showed a significant reduction in the protein expression of CYP1A2 (56%), 2C29 (31%), and 3A11 (37%) in CRF mice compared with control animals. Real-time PCR revealed a similar reduction in mRNA levels of CYP1A2, 2C29, and 3A11 (59, 56, and 37%, respectively), in CRF mice. There was no significant modification in protein expression and mRNA of CYP2D and 2E1. Compared with control animals, CRF mice displayed a 25% reduction in N-demethylation of erythromycin. For NAT2, protein expression decreased by 33% and mRNA levels decreased by 23%. In conclusion, this study demonstrates that protein expression of liver CYP1A2, CYP2C29, and CYP3A11 is down-regulated in CRF mice, secondary to reduced gene expression. Phase II enzymes are similarly affected by CRF. Our results will allow the use of knockout mice to determine the mechanism underlying CRF-induced down-regulation of liver drug-metabolizing enzymes.

Two parasites were found in the hyperiid amphipod Themisto libellula sampled with nets and collected by sediment traps over the annual cycle in the Canadian Beaufort Sea. The trophozoites of the newly described gregarine Ganymedes themistos sp. n. infected the digestive tract of 60.2% of the T. libellula analyzed from net collections. An unidentified ciliate infected the body cavity of 4.4% of amphipods. G. themistos possessed the ball-like structure at the anterior end and the cup-like invagination at the posterior end that are typical of the genus Ganymedes. The frequency and severity (number of parasites host−1) of infection by G. themistos increased with the length of T. libellula in the range 8–20 mm, and leveled off at ca. 94% and 186 trophozoites host−1 on average in the range 20–34 mm. Spatially, gregarine infection was less severe (63 ± 100 G. themistos host−1) on the Slope than on the Mackenzie Shelf (110 ± 160) and in the Amundsen Gulf (132 ± 157). No evidence of an impact of trophozoite infection on the feeding and sexual maturation of the host was found. For a given size of T. libellula, infection by both parasites was more frequent in the traps than in the nets (G. themistos: 91.0% vs. 82.7%; ciliates: 16.3% vs. 6%). The 2.7 times higher infection frequency in the traps suggested that the ciliate parasite may kill its host.

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D-3 C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P < 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D-3 or 1 alpha-hydroxyvitamin D-3, respectively, suggesting impaired C-25-hydroxylation of vitamin D-3. Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms.

A 29-year-old man with idiopathic dilated cardiomyopathy received a single-chamber transvenous implantable cardioverter-defibrillator (ICD; model Atlas II VR V-168, St. Jude Medical, Inc., Sylmar, CA, USA) for secondary prevention. A tripolar lead (Riata 7002-65, St. Jude Medical) was implanted, with a sensed R-wave amplitude >12.0 mV, pacing threshold 0.7 V at 0.5 ms, and pacing impedance 691 Ω. Two consecutive inductions of ventricular fibrillation (VF) were successfully terminated by 20-J shocks, with shock impedance of 48 Ω. The VF detection rate was programmed to ≥200 bpm, and a ventricular tachycardia zone was set to 180 to 200 bpm. Sensitivity was nominally programmed to 0.3 mV.

Cytochrome P450 (CYP) functional expression is reduced in uremia and normalized after restoration of kidney function via transplantation. The aim of this study was to evaluate the effect of conventional hemodialysis on the functional expression of CYP1A, 2C, and 3A. We also investigated the role of nuclear factor-κB (NF-κB) in CYP regulation during uremia. Primary cultures of normal rat hepatocytes were incubated with serum obtained from end-stage renal disease patients pre- and post-hemodialysis and healthy control subjects, in the presence and absence of the NF-κB inhibitor andrographolide. Uremic pre-hemodialysis serum caused significant reductions (P<0.01) in CYP1A (44%), 2C (27%), and 3A (35%) protein expression compared to control serum, while dialyzed serum (i.e., obtained immediately post-hemodialysis) had no effect. CYP1A2, 2C11, and 3A2 mRNA expression, as well as CYP3A activity, were similarly impacted by uremic serum and were improved to >80% of control values after hemodialysis. NF-κB inhibition nearly eliminated the effect of uremic serum on CYP functional expression. This is the first study to demonstrate that conventional hemodialysis acutely improves altered CYP functional expression observed in rat hepatocytes incubated with uremic human serum.

Drug metabolism can be affected by chronic renal failure (CRF). Although it is known that several drugs that are known to be acetylated accumulate in CRF, the effect of CRF on N-acetyltransferase (NAT), the enzyme responsible for this acetylation, is unknown. Herein is reported that protein and gene expression of both Nat isoforms in the liver was reduced by >30% and Nat2 activity was reduced by 50% in rats with CRF compared with control rats. Incubation of hepatocytes with serum from rats with CRF suggested that a circulating factor is responsible for the decrease in protein and gene expression. For testing the hypothesis that parathyroid hormone may be this factor, CRF was induced in parathyroidectomized rats; downregulation of Nat expression and activity was not observed in these rats. Furthermore, addition of parathyroid hormone to cultured hepatocytes induced a decrease in Nat2 protein and gene expression. In conclusion, liver acetylation of drugs in a rat model of CRF is reduced by a downregulation of Nat1 and Nat2 isoforms, secondary to decreased gene expression. Parathyroid hormone seems to be an important mediator of this phenomenon.

Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.

We address spatial and temporal distribution of abundance, lipid and caloric content and water column energy density of the copepod Calanus finmarchicus, a major food source for the north Atlantic right whale (NARW) Eubalaena glacialis in a primary feeding habitat — Grand Manan Basin, Bay of Fundy. The focus is on the lipid-rich diapausing copepodite stage 5 (C5) that dominates the zooplankton community during the summer and autumn whale-feeding period. We show that from May through July 2002, monthly averages of depth-integrated zooplankton wet biomass ( 0.88, p < 0.05) to the abundance and quality (i.e. energy density) of food available in the habitat. Thus, a water column-integrated energy density of 3 kJ m -3 appears to be a reasonable minimum estimate of that needed to define a right whale feeding habitat, though subject to spatial and temporal variation. Accordingly, inter-annual variation in the abundance and energy content of C5s will influence right whale feeding success and may influence arrival at and departure to and from, as well as seasonal residency in, primary feeding habitats. We suggest that prey field examinations and estimates of the type presented here should advance insights concerning the nature and location of other potential habitats as well as variation in right whale condition and reproductive capacity.

Chronic renal failure (CRF) is associated with a decrease in liver drug metabolism, particularly mediated by the cytochrome P450. CRF also impedes intestinal drug transporters [mainly P-glycoprotein (P-gp) and multidrug resistance protein (MRP)]. However, very few studies have evaluated the effects of CRF on liver drug transport. The present study aimed to investigate the repercussions of CRF on liver drug transporters involved in hepatic uptake [organic anion transporting polypeptide (Oatp) 2] and in drug extrusion (P-gp and MRP2). Two groups of rats were studied: control and CRF. Oatp2, P-gp, and MRP2 protein expressions and mRNA levels, as well as some of their metabolic activity, were assessed. The effects of CRF serum on drug transporters were also evaluated in cultured hepatocytes. Compared with control, creatinine clearance was reduced by 70% (p < 0.01) in rats with CRF. Protein expression and mRNA levels of P-gp were increased by 25 and 40% (p < 0.01), respectively, in liver from rats with CRF. MRP2 protein expression was identical in both groups, whereas its mRNA levels were increased by 35% (p < 0.01) in CRF rats. Finally, Oatp2 protein expression was reduced by 35%, whereas its mRNA levels remained unchanged. Similar results were obtained when hepatocytes were incubated with uremic serum. In conclusion, CRF is associated with a decrease in liver transporters involved in drug absorption and an increase in those involved in drug extrusion. Uremic mediators appear to be responsible for these modifications.