The binding of adenine derivatives to Na(+)-montmorillonite increases in the order 5'AMP, 3'-AMP, 5'ADP < adenosine < purine, adenine. With the exception of cytosine, cytosine derivatives bind less strongly than the corresponding adenine derivatives in the order 5'-CMP < cytidine < cytosine. There is little difference in the binding of uracil derivatives and these compounds bind less strongly than the corresponding adenine analogs. It is concluded that the adenine ring in adenine derivatives is protonated by the acidic montmorillonite surface and binding is a consequence of the electrostatic interaction between the protonated base and the negative charges on the surface of the montmorillonite. Different binding trends were observed with Cu(2+)-montmorillonite with AMP binding more strongly than adenosine and UMP binding more strongly than uridine. It is concluded that ligation to the Cu2+ is a major force in the binding of nucleotides to Cu(2+)-montmorillonite and are not readily washed from the clay. Factors contributing to the binding are discussed. Watson-Crick hydrogen bonding of 5'-AMP to poly(U) and 5'GMP to poly(C) was observed when the homopolymers are bound to the surface of the clay. No association of 5'-UMP to poly(U) bound to clay was detected. The possible role of montmorillonite clays in the prebiotic formation of RNA is discussed.

A simulation of the organic layer accreted onto interstellar dust particles was prepared by slow deposition of a CO:NH2:H2O gas mixture on an Al block at 10 K, with concomitant irradiation with vacuum UV. The residues were analyzed by GC-MS, HPLC, and near IR; a reaction pathway leading from NH3 to complex alcohol, fatty acid, and amide products in 27 stages is postulated. The astronomical relevance and significance of the observations are discussed.

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. There is increasing interest in the possible role of newer fluoroquinolone antibiotics in the treatment of drug-susceptible tuberculosis. In a murine model of tuberculosis treatment, the substitution of moxifloxacin for isoniazid allows treatment to be shortened from 6 months to 4 months (10). Moxifloxacincontaining regimens are currently being evaluated in phase II treatment trials (1; Tuberculosis Trials Consortium Study 28). Moxifloxacin undergoes phase II biotransformation by two pathways: (i) sulfate conjugation, with the resultant metabolite (M1 conjugate) accounting for 38% of an oral dose of moxifloxacin, and (ii) glucuronide conjugation, with the resultant metabolite (M2 conjugate) accounting for 14% of an oral dose (16). The CYP450 system does not play a role in moxifloxacin metabolism. Although best known for its effects on the CYP450 system, rifampin can also up-regulate the phase II metabolic glucuronidation pathway (5).P-glycoprotein is a protein found in the intestinal mucosa, liver, and kidney that plays an important role in the absorption, distribution, and elimination of xenobiotics (8). The multidrug resistance gene (MDR1) codes for P-glycoprotein, and polymorphisms in the MDR1 gene can lead to altered P-glycoprotein function. For example, subjects homozygous for the MDR1 C3435T polymorphism had lower intestinal P-glycoprotein concentrations and higher plasma digoxin concentrations (6, 7). P-glycoprotein is induced by rifampin (9, 12). This observation suggests another possible mechanism for a rifampin-induced drug-drug interaction. We evaluated the effects of rifampin and MDR1 C3435T polymorphisms on the pharmacokinetics of moxifloxacin.The primary objective of the study was to compare the pharmacokinetics of daily moxifloxacin without and with coadministration of rifampin. A secondary objective was to characterize the effects of MDR1 C3435T polymorphisms on moxifloxacin pharmacokinetics.(Some of the results of this study have been reported previously in abstract form [18]). MATERIALS AND METHODSExperimental design. This was a single-center, two-period, open-label, sequential-design pharmacokinetic study. The first pharmacokinetic sampling was performed with the fourth daily dose of oral moxifloxacin (400 mg once daily). Rifampin (600 mg once-daily, given at the same time as moxifloxacin) was then added, and a second sampling was performed with the 10th dose of rifampin (the 14th dose of daily moxifloxacin). The st...

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C max) and the area under the concentration-time curve from 0 to 24 h (AUC0–24) were 3.4 mg/liter and 30.2 mg · h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg · h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the meanC max/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC andC max/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

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