Effect of Concomitant Medications Affecting Gastric pH and Motility on Posaconazole Tablet Pharmacokinetics

Poster presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy (52nd ICAAC) held in San Francisco 9/9-9/12 Background: Posaconazole (POS) oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new POS tablet formulation has demonstrated improved bioavailability over oral suspension in healthy adults in the fasting state. This study evaluated the effect of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and motility (metoclopramide) on the pharmacokinetics of POS tablet. Methods: This was a prospective, open-label, 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg (100 mg x 4) dose of POS tablets was administered alone or with 20 mL antacid (Mylanta® Ultimate Strength Liquid, aluminum hydroxide 2 g and magnesium hydroxide 2 g), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was ≥10-day washout between treatment periods. Results: POS exposure, Tmax, and t½ were similar when administered alone or with medications affecting gastric pH and motility. Geometric mean ratios (90% CI) of AUC0-last compared with those of POS alone were antacid, 1.04 (0.90–1.20); ranitidine, 0.97 (0.84–1.12); esomeprazole, 1.02 (0.88–1.17); and metoclopramide, 0.93 (0.80–1.07). Geometric mean ratios (90% CI) of Cmax compared with those of POS alone were antacid, 1.06 (0.90–1.26); ranitidine, 1.04 (0.88–1.23); esomeprazole, 1.05 (0.89–1.24); and metoclopramide, 0.86 (0.73–1.02). Conclusions: In healthy volunteers, the pharmacokinetics of a single dose of POS tablet 400 mg were similar when administered alone or with medications affecting gastric pH or motility

Biochemical warfare on the reef : the role of glutathione transferases in consumer tolerance of dietary prostaglandins

© 2010 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 5 (2010): e8537, doi:10.1371/journal.pone.0008537.Despite the profound variation among marine consumers in tolerance for allelochemically-rich foods, few studies have examined the biochemical adaptations underlying diet choice. Here we examine the role of glutathione S-transferases (GSTs) in the detoxification of dietary allelochemicals in the digestive gland of the predatory gastropod Cyphoma gibbosum, a generalist consumer of gorgonian corals. Controlled laboratory feeding experiments were used to investigate the influence of gorgonian diet on Cyphoma GST activity and isoform expression. Gorgonian extracts and semi-purified fractions were also screened to identify inhibitors and possible substrates of Cyphoma GSTs. In addition, we investigated the inhibitory properties of prostaglandins (PGs) structurally similar to antipredatory PGs found in high concentrations in the Caribbean gorgonian Plexaura homomalla. Cyphoma GST subunit composition was invariant and activity was constitutively high regardless of gorgonian diet. Bioassay-guided fractionation of gorgonian extracts revealed that moderately hydrophobic fractions from all eight gorgonian species examined contained putative GST substrates/inhibitors. LC-MS and NMR spectral analysis of the most inhibitory fraction from P. homomalla subsequently identified prostaglandin A2 (PGA2) as the dominant component. A similar screening of commercially available prostaglandins in series A, E, and F revealed that those prostaglandins most abundant in gorgonian tissues (e.g., PGA2) were also the most potent inhibitors. In vivo estimates of PGA2 concentration in digestive gland tissues calculated from snail grazing rates revealed that Cyphoma GSTs would be saturated with respect to PGA2 and operating at or near physiological capacity. The high, constitutive activity of Cyphoma GSTs is likely necessitated by the ubiquitous presence of GST substrates and/or inhibitors in this consumer's gorgonian diet. This generalist's GSTs may operate as ‘all-purpose’ detoxification enzymes, capable of conjugating or sequestering a broad range of lipophilic gorgonian compounds, thereby allowing this predator to exploit a range of chemically-defended prey, resulting in a competitive dietary advantage for this species.Financial support for this work was provided by the Ocean Life Institute Tropical Research Initiative Grant (WHOI) to KEW and MEH; the Robert H. Cole Endowed Ocean Ventures Fund (WHOI) to KEW; the National Undersea Research Center - Program Development Proposal (CMRC-03PRMN0103A) to KEW; Walter A. and Hope Noyes Smith, and a National Science Foundation Graduate Research Fellowship to KEW