Comparative Pharmacokinetics and Tissue Concentrations of Flunixin Meglumine and Meloxicam in Tilapia (Oreochromis spp.)

Evidence of pain perception in fish is well established, but analgesic use in aquaculture is limited. The objective was to investigate the comparative pharmacokinetics of flunixin administered intramuscularly (IM) and meloxicam administered IM or orally (PO) in tilapia. Two hundred and seventy fish were assigned to 1 of 3 treatment groups: flunixin meglumine IM (2.2 mg/kg); meloxicam IM (1 mg/kg); or meloxicam PO (1 mg/kg). Blood and tissue samples were collected from 6 fish per treatment at 14 time points for 10 days. Drug concentrations were determined using ultra-high-pressure liquid chromatography coupled with mass spectroscopy. Plasma concentration versus time data were analyzed with a non-compartmental approach using a commercially available software. Flunixin reached a mean maximum concentration (Cmax) of 4826.7 ng/mL at 0.5 h, had a terminal half-life (T1/2) of 7.34 h, and an area under the concentration–time curve extrapolated to infinity (AUCINF_obs) of 25,261.62 h·ng/mL. Meloxicam IM had a T1/2 of 9.4 h after reaching a Cmax of 11.3 ng/mL at 2 h, with an AUCINF_obs of 150.31 h·ng/mL. Meloxicam PO had a T1/2 of 1.9 h after reaching a Cmax of 72.2 ng/mL at 2 h, with an AUCINF_obs of 400.83 h·ng/mL. Tissue concentrations of both drugs were undetectable by 9 h. Flunixin reached a sufficient plasma concentration to potentially have an analgesic effect, while meloxicam, when administered at the given dosage, likely would not.

Vitamins as Possible Cancer Biomarkers: Significance and Limitations

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as ‘hidden hunger’), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)

Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in Abcb1a/1b-/- mice and by 6.2- and 6.4-fold in Abcb1a/1b;Abcg2-/- mice, respectively. Oatp1a/1b deficiency did not alter selpercatinib pharmacokinetics. The ABCB1/ABCG2 inhibitor elacridar boosted selpercatinib brain penetration in wild-type mice to the levels seen in Abcb1a/1b;Abcg2-/- mice. Cyp3a-/- mice showed a 1.4-fold higher plasma AUC0–4h than wild-type mice, which was then 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. In summary, ABCG2, and especially ABCB1, limit brain and testis penetration of selpercatinib. Elacridar coadministration could mostly reverse these effects, without causing acute toxicity. CYP3A-mediated metabolism can limit selpercatinib oral exposure and hence its tissue concentrations. These insights may be useful in the further clinical development of selpercatinib.

510 Late-Breaking: Dietary Glycine Supplementation During Growing and Finishing Phases Increases Tissue Concentrations of Total Creatine and Gene Expression of Creatine-synthetic Enzymes in Low-birthweight Pigs

Dietary glycine is required for maximum growth and development in animals by stimulating muscle protein synthesis and as a component of creatine. Creatine is synthesized from glycine, arginine, and S-adenosylmethionine by arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). Sufficient creatine synthesis for growth requires adequate substrate supply. However, swine diets are deficient in glycine. Additionally, intrauterine growth restricted (IUGR) pigs have reduced glycine synthesis. This results in decreased creatine synthesis and lower total creatine content in tissues, leading to reduced cellular energy metabolism and diminished muscle protein accretion. This study was designed to test the hypothesis that dietary glycine supplementation in corn-and-soybean-meal-based diets would improve overall growth and skeletal muscle accretion in post-weaning IUGR pigs by increasing the expression of creatine-synthetic enzymes and tissue concentrations of total creatine. Fourteen IUGR pigs (birthweight = 0.98±0.03 kg, mean±SEM) and 20 normal birthweight pigs (birthweight = 1.44±0.02 kg, mean±SEM) were obtained at weaning for this study. Pigs from each birthweight group were randomly assigned to 1% glycine + 0.19% corn starch treatment group or 1.19% alanine group (isonitrogenous control) for the study (21 d to 188 d of age); tissues were collected at d 188. Data were analyzed by using 2-way ANOVA and the Duncan multiple comparison test. Glycine-supplemented IUGR pigs had greater tissue concentrations of creatine, creatinine, and creatine phosphate than control IUGR in all tissues measured (P< 0.05). Control IUGR pigs showed diminished activity and mRNA expression of creatine-synthetic enzymes (P < 0.05); this was mitigated by glycine supplementation as glycine supplemented IUGR pigs showed normal levels of enzyme activity and mRNA expression. Overall, results of this study indicate dietary glycine supplementation to IUGR pigs between weaning and market weight effectively restores creatine-synthetic enzyme activities and increase tissue concentrations of total creatine, leading to increased lean tissue growth. (Supported by USDA-NIFA)

Forage productivity and chemical composition of Megathyrsus maximus cv. Tamani under defoliations regimes

The effects of defoliation frequency (21, 28, 35 and 42 days) and defoliation intensity (20, 30 and 40 cm above the ground) on green dry matter (GDM) yield, and chemical composition of Megathyrsus maximus cv. Tamani were evaluated under natural field conditions at the Roraima´s savannas. Defoliation regimes affect productivity and chemical composition of M. maximus cv. Tamani forage. The decrease in the pasture defoliation frequency and intensity improved the accumulation of forage, however it reduces the tissue concentrations of N, P, Ca, Mg and K. Irrespective of defoliation frequencies, the highest levels of N (25.31 g kg-1), P (2.11 g kg-1), Mg (2.78 g kg-1) and K (21.13 g kg-1) were recorded for the defoliation intensity at 40 cm above the ground, except for Ca (4.31 g kg-1), where the greatest concentration was obtained with defoliations at 30 cm above the ground. The use of defoliation frequency around 32 days and defoliation intensity of 28 cm above the ground can be considered adequate for the management of pastures of M. maximus cv. Tamani, in order to provides higher forage productivity and quality, regrowth vigor, larger efficiency of forage utilization, greater tissue renewal and canopy structure more favorable to grazing.

Kidney and Liver Tissue Tacrolimus Concentrations in Adult Transplant Recipients—The Influence of the Whole Blood and Tissue Concentrations on Efficiency of Treatment during Immunosuppressive Therapy

Tacrolimus (TAC) has a narrow therapeutic index and highly variable pharmacokinetic characteristics. Close monitoring of the TAC concentrations is required in order to avoid the risk of acute rejection or adverse drug reaction. The results in some studies indicate that inter-tissue TAC concentrations can be a better predictor with regards to acute rejection episode than TAC concentration in whole blood. Therefore, the aim of the study was to assess the correlation between dosage, blood, hepatic and kidney tissue concentration of TAC measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) and clinical outcomes in a larger cohort of 100 liver and renal adult transplant recipients. Dried biopsies were weighed, mechanically homogenized and then the samples were treated with a mixture of zinc sulfate—acetonitrile to perform protein precipitation. After centrifugation, the extraction with tert-butyl methyl ether was performed. The analytical range was proven for TAC tissue concentrations of 10–400 pg/mg. The accuracy and precision fell within the acceptance criteria for intraday as well as interday assay. There was no correlation between dosage, blood (C0) and tissue TAC concentrations. TAC concentrations determined in liver and kidney biopsies ranged from 8.5 pg/mg up to 160.0 pg/mg and from 7.1 pg/mg up to 215.7 pg/mg, respectively. To the best of our knowledge, this is the first LC-MS/MS method for kidney and liver tissue TAC monitoring using Tac13C,D2 as the internal standard, which permits measuring tissue TAC concentrations as low as 10 pg/mg.