The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro.

PLD-118 is a novel, oral antifungal drug, under development for the treatment of Candida infections. Possible metabolism of PLD-118 by rat, dog and human S9 liver homogenates and inhibition of human cytochrome P450 (CYP) enzymes were investigated. PLD-118 (10 and 100 microM) incubated for 0-60 min with S9 fractions and NADPH was determined by HPLC, using the Waters AccQ.Tag method after derivatization of amino acids to stable, fluorescent derivatives. CYP assays were performed using pooled human liver microsomes with substrates, selective towards human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, incubated at concentrations around the Km. Incubation mixtures were preincubated with PLD-118 (0.1-100 microM) or control inhibitor for 5 min. No metabolism of PLD-118 was detected with rat and dog S9 fractions. A small (8%) decrease in PLD-118 at 100 microM (not detected at 10 microM) with human microsomes was considered to be biologically irrelevant. PLD-118 did not inhibit any of the tested CYPs. PLD-118, at concentrations up to 100 microM, is not metabolized by rat, dog or human liver S9 homogenates and does not inhibit human CYPs in vitro, suggesting little likelihood for interaction of PLD-118 with drugs metabolized by these enzymes.

Effect of a vegan diet on biomarkers of chemoprevention in females.

1. In order to study the potential beneficial effects of a vegan diet, a cross-sectional study was performed and several biomarkers of chemoprevention were measured in a population of female 'living food' eaters ('vegans'; n = 20) vs matched omnivorous controls (n = 20). 2. White blood cells obtained from fresh blood samples were subjected to the single-cell gel-electrophoresis assay. There was no statistically significant difference between the vegans and controls in the parameters 'tail length' and 'tail moment'. However, the 'tail moment' was significantly lower in a subset of the vegans (i.e.in those who did not use any vitamin and/or mineral supplements). 3. Fresh blood samples were exposed in vitro to the mutagen mitomycin C just prior to culturing. After culturing the number of binucleated lymphocytes with micronuclei was scored. There was no difference between the controls and vegans in the incidence of baseline micronuclei, nor in the number of mitomycin C-induced micronuclei. However, a significant correlation (r = -0.64, P < 0.01) between the number of mitomycin C-induced micronuclei and the activity of erythrocyte superoxide dismutase was found in the vegans. The number of baseline micronuclei increased with age in both groups. These findings may be of biological relevance. 4. The content of glutathione-S-transferase-alpha in plasma was not different between the vegans (n = 12) and controls (n = 12). 5. The present data indicate a few differences in biomarkers of chemopreventive potential in strict vegans vs matched omnivorous controls. The significance of these changes as biologically relevant indicators of beneficial effects of vegan diets in humans needs to be determined in studies with a larger number of subjects.

Vitamin B-6 metabolism in the pregnant rat: effect of progesterone on the (re)distribution in maternal vitamin B-6 stores.

Parameters of vitamin B-6 metabolism were studied in pregnant rats, nonpregnant control rats and progesterone-supplemented ovariectomized rats. Plasma pyridoxal 5'-phosphate (PLP) and pyridoxal concentrations in pregnant rats were 20 and 40% of those of nonpregnant rats, respectively. Excretion of 4-pyridoxic acid in the urine in pregnant rats was about 40% of that of nonpregnant rats. Liver PLP content was also lower during pregnancy, but liver pyridoxamine 5'-phosphate (PMP), kidney PLP and PMP and muscle PLP contents did not change significantly. Progesterone administration to ovariectomized rats resulted in slightly lower plasma, liver and kidney PLP levels than in intact untreated control rats. Liver and kidney pyridoxal kinase (PK) and pyridoxamine 5'-phosphate oxidase activities were similar in pregnant and nonpregnant rats. Progesterone treatment resulted in a significantly lower PK activity in the kidney of the treated rats than in untreated controls. It is concluded that the pregnancy-induced changes in vitamin B-6 metabolism were unlikely to be related directly to progesterone. However, progesterone may secondarily affect maternal vitamin B-6 stores during pregnancy, by temporary deposition and increased retention of vitamin B-6.