No abstract

Intestinal transporters are crucial determinants in the oral absorption of many drugs. We therefore studied the mRNA expression (N = 33) and absolute protein content (N = 10) of clinically relevant transporters in healthy epithelium of the duodenum, the proximal and distal jejunum and ileum, and the ascending, transversal, descending, and sigmoidal colon of six organ donors (24-54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2 and 1.6 pmol/mg with the exception of those of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6-4.9 pmol/mg) that accounted for ∼50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1, and ASBT were significantly more abundant in jejunum and ileum than in colon. In contrast to this, the level of expression of ABCC2, ABCC3, and OCT3 was found to be highest in colon. Site-dependent differences in the levels of gene and protein expression were observed for ABCB1 and ASBT. Significant correlations between mRNA and protein levels have been found for ABCG2, ASBT, OCT3, and PEPT1 in the small intestine. Our data provide further physiological pieces of the puzzle required to predict intestinal drug absorption in humans.

This work revises and complements existing findings on the distribution of drug-metabolizing enzymes in the first-pass effect organs. We explored gene expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography/ tandem mass spectrometry) of CYP1A2, CYP2B6, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4/5, UGT1A1/3, UGT2B7/15 in the liver, duodenum, jejunum, ileum, and colon in paired tissues from nine organ donors. All proteins were detected in the liver, but in the intestine CYP2C9/19, CYP2D6, CYP3A4/5, UGT1A1/3, and UGT2B7 were found. CYP3A4 showed comparable abundance in the liver and jejunum, whereas other enzymes were markedly higher in the hepatic tissue. Nearly all detected enzymes showed their highest abundance in the jejunum. Significant correlations between mRNA and protein levels in liver or intestine were found for most enzymes. CYP3A4 and CYP3A5 protein abundance, but not other enzymes, were significantly correlated in the liver and the small intestine. Our data may contribute to an improved understanding of hepatic and intestinal drug metabolism.

Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. Therefore, we explored adenosine triphosphate–binding cassette (ABC) and solute carriers family transporters expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography tandem mass spectrometry (LC‐MS/MS)) in human liver and duodenum, jejunum, ileum, and colon in paired tissue specimens from nine organ donors. The transporter proteins were detected in the liver (permeability‐glycoprotein (P‐gp), multidrug resistance protein (MRP)2, MRP3, breast cancer resistance protein (BCRP), organic anion‐transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic cation transporter (OCT)1, OCT3, organic anion transporter 2, Na+‐taurocholate cotransporting polypeptide, monocarboxylate transporter (MCT)1, and multidrug and toxin extrusion 1) and the intestine (P‐gp, multidrug‐resistance protein (MRP)2, MRP3, MRP4, BCRP, OATP2B1, OCT1, apical sodium–bile acid transporter (only ileum), MCT1, and peptide transporter (PEPT1)). Significantly higher hepatic gene expression and protein abundance of ABCC2/MRP2, SLC22A1/OCT1, and SLCO2B1/OATP2B1 were found, as compared to all intestinal segments. No correlations between hepatic and small intestinal protein levels were observed. These observations provide a description of drug transporters distribution without the impact of interindividual variability bias and may help in construction of superior physiologically based pharmacokinetic and humanized animal models.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC 0-24 of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC 0-24 and C min for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

The eastern boundary circulation off the coast of Angola has been described only sparsely to date, although it is a key element in the understanding of the highly productive tropical marine ecosystem off Angola. Here, we report for the first time direct velocity observations of the Angola Current (AC) at ∼11°S collected between July 2013 and October 2015 in the depth range from 45 to 450 m. The measurements reveal an alongshore flow that is dominated by intraseasonal to seasonal variability with periodically alternating southward and northward velocities in the range of ±40 cm/s. During the observation period, a weak southward mean flow of 5–8 cm/s at 50 m depth is observed, with the southward current extending down to about 200 m depth. Corresponding mean southward transport of the AC is estimated to be 0.32 ± 0.046 Sv. An extensive set of hydrographic measurements is used to investigate the thermal structure and seasonality in the hydrography of the eastern boundary circulation. Within the depth range of the AC, the superposition of annual and semiannual harmonics explains a significant part of the total variability, although salinity in the near surface layer appears to be also impacted by year‐to‐year variability and/or short‐term freshening events. In the central water layer, temperature and salinity on isopycnals vary only weakly on seasonal to annual time scales. The available data set is further used to evaluate different reanalysis products particularly emphasizing the ocean's role in coupled climate model SST biases in the Eastern Tropical Atlantic.

The eastern boundary region off Angola encompasses a highly productive ecosystem important for the food security of the coastal population. The fish-stock distribution, however, undergoes large variability on intraseasonal, interannual, and longer time scales. These fluctuations are partly associated with large-scale warm anomalies that are often forced remotely from the equatorial Atlantic and propagate southward, reaching the Benguela upwelling off Namibia. Such warm events, named Benguela Niños, occurred in 1995 and in 2011. Here we present results from an underexplored extensive in situ dataset that was analyzed in the framework of a capacity-strengthening effort. The dataset was acquired within the Nansen Programme executed by the Food and Agriculture Organization of the United Nations and funded by the Norwegian government. It consists of hydrographic and velocity data from the Angolan continental margin acquired biannually during the main downwelling and upwelling seasons over more than 20 years. The mean seasonal changes of the Angola Current from 6° to 17°S are presented. During austral summer the southward Angola Current is concentrated in the upper 150 m. It strengthens from north to south, reaching a velocity maximum just north of the Angola Benguela Front. During austral winter the Angola Current is weaker, but deeper reaching. While the southward strengthening of the Angola Current can be related to the wind forcing, its seasonal variability is most likely explained by coastally trapped waves. On interannual time scales, the hydrographic data reveal remarkable variability in subsurface upper-ocean heat content. In particular, the 2011 Benguela Niño was preceded by a strong subsurface warming of about 2 years’ duration.