Pharmacokinetic study of rifaximin after oral administration in healthy volunteers.

Eighteen healthy male volunteers, with a mean age of 24 yrs (range 18-40), underwent an open pharmacokinetics study, aimed at detecting rifaximin concentration in blood and urine after a single oral administration of 400 mg of the antibiotic. Administration took place after a 9 hours' fast and was followed by a breakfast after 2 hours and a lunch after 5 hours. Blood samples were collected before rifaximin administration and 1, 2, 4, 8, 12, 24 and 48 hours after dosing. Urine samples were collected immediately before dosing (reference sample) and then at the end of the following intervals of time: 0-6 h, 6-12 h, 12-24 h, 24-48 h. During the whole study period, the local and general tolerance to rifaximin administration was checked. Rifaximin concentration was assessed by reversed phase high performance liquid chromatography with electrochemical detection. In almost every plasma sample, rifaximin concentration was undetectable (lower than the detection limit of the analytical method, i.e. 2 ng/ml). In urine, very small amounts of the unchanged molecule (< 0.01% of the administered dose) were found in the period 0-48 hours. These results confirm the negligible absorption by the intestinal tract of a single oral dose of rifaximin (400 mg). Local and general tolerance of the administered drug was very good.

Determination of exifone in human plasma and urine by high-performance liquid chromatography with electrochemical detection.

A high-performance liquid chromatographic method with electrochemical detection was developed for the determination of exifone in human plasma and urine. Exifone was extracted from acidified plasma or neutralized urine with diethyl ether and the evaporated extracts were analysed on a C18 reversed-phase column. The compound was eluted in about 8 min with acetonitrile-0.3 M orthophosphoric acid (15:85, v/v) at a flow-rate of 0.9 ml/min. This method gave accurate and reproducible results; the calibration graphs were linear (r greater than 0.99) over the range of 2.8-360 nmol/l for plasma and 0.18-36 mumol/l for urine, and concentrations as low as 1 nmol/l in plasma could be quantified. These results allowed this assay to be used for determinations in single-dose pharmacokinetic studies.

Endogenous production of prothymocyte differentiating activity by phytohemagglutinin-stimulated T-cell-depleted human marrow.

The PHA responsiveness of marrow T-cell precursors remains a matter of controversy. We have investigated the capacity of human marrow to proliferate under phytohemagglutinin (PHA) stimulation following extensive removal of mature T cells by complement-dependent cytotoxicity with MBG6 and RFT8 monoclonal antibodies. PHA-induced thymidine uptake by marrow cells occurred with a peak on Days 6-8 of incubation instead of Day 3 for PBL. This peak was observed 48 hr earlier in the presence of PHA-stimulated T-depleted marrow cell supernatants. These supernatants can also promote the growth of mature T-cell colonies from MBG6-, RFT8-, T11-, T3- marrow. However, full colony development requires exogenous interleukin 2 (IL-2). IL-2 could be detected in marrow supernatants but only at very low levels and beyond Days 3 and 4. In contrast Days 1-6 marrow supernatants were equally effective in promoting MBG6-RFT8- marrow cell responsiveness to PHA. We conclude that marrow T-cell precursors are not PHA responsive and that PHA induces the production by marrow non-T cells of a prothymocyte-differentiating activity (PTDA); PTDA can differentiate marrow T-cell progenitors into PHA-responsive T cells; following activation by PHA, these cells undergo limited proliferation induced by IL-2 endogenously released from de novo differentiated T cells. It is suggested that this mechanism may account for extrathymic differentiation of the T-cell lineage in heavily irradiated marrow transplantation recipients.

In vitro effects of sodium diethyldithiocarbamate (Imuthiol) on human T lymphocytes.

The effect of purified diethyldithiocarbamate, DTC (Imuthiol) on human T-cell dependent functions has been investigated. The mitogenic response of PHA-stimulated peripheral blood lymphocytes (PBL) was significantly enhanced by Imuthiol at low drug concentration (10(-7) mg/ml). The same dose of Imuthiol also stimulated IL2 production by human PBL. This enhancement depended on the presence of adherent cells. These results could, in part, explained the immunostimulant activity of Imuthiol.

Pharmacokinetics and metabolism of the novel anticonvulsant agent N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in rats and humans.

N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) belongs to a new series of experimental anticonvulsants related to lidocaine. This study was undertaken to understand the pharmacokinetics and metabolism of D2624 in rats and humans, with emphasis on the possible formation of 2,6-dimethylaniline (2,6-DMA). After oral administration of stable isotope-labeled parent drug to rats and GC/MS analysis of plasma samples, two metabolites were identified: D3017, which is the primary alcohol, and 2,6-DMA, formed by amide bond hydrolysis of either D2624 or D3017. In urine, three metabolites of D2624 were identified: namely D3017,2,6-DMA, and D3270 (which is the carboxylic acid derivative of D3017). Based on plasma AUC analysis, D3017 and 2,6-DMA accounted for > 90% of the dose of D2624. After oral administration, D2624 was found to be well absorbed (93%), but underwent extensive first-pass metabolism in the rat, thus resulting in 5.3% bioavailability. Rat and human liver microsomal preparations were capable of metabolizing D2624 to D3017 and 2,6-DMA. The formation of D3017 was NADPH-dependent, whereas 2,6-DMA formation was NADPH-independent and probably was catalyzed by amidase(s) enzymes. In a single-dose (25-225 mg) human volunteer study, the parent drug (D2624) was not detected in plasma at any dose, whereas 2,6-DMA was detected only at the two highest doses (150 and 225 mg). D3017 was detected after all doses of parent drug, with approximate dose proportionality in AUC and a half-life of 1.3-2.2 hr. The metabolic behavior observed in humans suggests there is a marked species difference in the oxidative and hydrolytic pathways of D2624.