Nanostructure initiator mass spectrometry (NIMS) is a recently introduced matrix-free desorption/ionization platform that requires minimal sample preparation. Its application to xenobiotics and endogenous metabolites in tissues is demonstrated, where clozapine and N-desmethylclozapine were observed from mouse and rat brain sections. It has also been applied to direct biofluid analysis where ketamine and norketamine were observed from plasma and urine. Detection of xenobiotics from biofluids was made even more effective using a novel NIMS on-surface extraction method taking advantage of the hydrophobic nature of the initiator. Linear response and limit of detection were also evaluated for xenobiotics such as methamphetamine, codeine, alprazolam, and morphine, revealing that NIMS can be used for quantitative analysis. Overall, our results demonstrate the capacity of NIMS to perform sensitive, simple, and rapid analyses from highly complex biological tissues and fluids.

Two experiments were conducted to study the effect of intake of fiber on productive performance of high producing dairy goats during early to midlactation. Four dietary treatments were isonitrogenous and consisted of combinations of chopped alfalfa hay and concentrate, yielding 14, 18, 22, and 26% ADF. In Experiment 1, 40 multiparous Alpine does were used in a completely randomized block design. Milk fat content and total chewing time increased, and milk yield tended to decrease, as dietary ADF intake increased. Chewing efficiency [min/(g x kg BW.75)] for DM decreased, whereas that for ADF increased as ADF intake increased. Prediction equations were the following: milk fat yield, g/d = 115.78 - .128 x ADF intake, g/d + .00021 X (ADF intake)2 (r = .55); total chewing time, min/d = 345.33 + .32 x ADF intake, g/d (r = .60). In Experiment 2, 20 does were used in a completely randomized design. Apparent digestibilities of DM and energy decreased as dietary ADF intake increased. Rumen turnover rate and transit time of liquid were affected by ADF intake. Transit time of hay decreased as ADF intake increased. Intake of ADF affected pH and ammonia, acetate, and butyrate concentrations in the rumen. Acetate to propionate ration increased with ADF intake. No apparent trends were observed in whole blood beta-hydroxybutyrate or in plasma NEFA concentrations related to ADF intake. It appeared that DMI and milk fat yield leveled at 22% ADF or 43% NDF. For lactating dairy goats producing more than 3.5 kg/d of milk, calculated fat output reached a plateau when they consumed 587 g/d of ADF and spent 512 min/d chewing.

Growing goats, 45 Alpine and 45 Nubian, were used in a 3 x 3 factorial arrangement to quantify the influence of dietary energy and protein levels on daily DM intake and nutrient utilization for growth. Goats had ad libitum access to complete mixed diets containing either 2.46, 2.77 or 3.05 Mcal/kg ME plus 11.2, 12.7 or 15.1% CP for 16 wk. Dry matter intake decreased curvilinearly as dietary ME density increased (P less than .001). Dry matter intake increased linearly (P less than .05) as dietary CP level increased during all growth intervals except wk 25 to 28 of age. Average daily gain was 115, 113 and 99 g/d for goats fed diets containing 2.46, 2.77 and 3.05 Mcal/kg ME, respectively. Average daily gain was 104, 106 and 117 g/d for goats fed diets with 11.2, 12.7 and 15.1% CP, respectively. Dry matter intake was higher (P less than .01) for Alpine than for Nubian goats, whereas ADG was similar between breeds. Intake of ME was 248, 260 and 198 kcal/(kg.75.d) for goats fed the low- medium- and high-energy diets, respectively. Intake of CP was 9.1, 10.7 and 13.2 g/(kg.75.d) for goats fed low-, medium- and high-protein diets, respectively. Average requirements for growth derived from regression analysis of all data points were 4.6 kcal ME and .26 g CP/g ADG. The prediction equation for intake of growing goats of 4 to 8 mo of age was: DMI, g/d = 1,749 - 496 DE, kcal/g + 18 live weight, kg + 3 ADG, g/d; r2 = .73 (Sy.x = 127, P less than .0001, n = 90). The requirement of ME for growth was 33% lower than the value recommended in 1981 by the National Research Council.

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Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations (Cmax) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest Cmax values were in bone and eye lens (0.070 and 0.077 μg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose Cmax values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had Cmax values >25% higher than all other 1-h-postdose values. For 24-h-postdose Cmax values, only large intestine, large intestine mucosa, and urine had the highest Cmax values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.

ABSTRACT:The major circulating and excretory metabolites in mice, rats and monkeys were species-dependent; however, several common metabolites were observed in more than one species. In addition to parent torcetrapib, M1, M3, and M4 in rats, M4 and M17 in mice, and M3 and M8 in monkeys were detected as the major circulating metabolites. A mechanism for the formation of an unusual metabolite M28 has been proposed.

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