Pharmacokinetics of two spiroarsoranes administered intravenously or orally to rabbits.

The pharmacokinetics of two spiroarsorane molecules (1,2) were investigated after both intravenous bolus and an oral administration in rabbits. After iv administration of a 15-mg/kg dose, for the two substances, the plasma concentration-time curves were well described by an open two-compartmental model. The half-lives of the first phase were 0.47 +/- 0.12 and 0.27 +/- 0.02 h for 1 and 2, respectively. The half-lives of the terminal phase were of the same order of magnitude for the two substances: 4.38 +/- 0.24 and 6.03 +/- 1.14 h, respectively. Total plasma clearances were 2.47 +/- 0.44 and 0.81 +/- 0.04 L/h, respectively, and the steady-state volume of distribution of 2 (14.99 +/- 2.57 L) was larger than that of 1 (4.27 +/- 0.28 L). After oral administration, spiroarsorane 2 was not absorbed. The availability of the suspension of 1 was 18%. The rate of the absorption phase of 1 showed a saturation process, probably due to the solubility of the molecule. When increasing oral doses of 1 (15, 30, and 60 mg/kg) were administered, the plasma concentrations did not increase to the same extent.

Determination of diethylcarbamazine, an antifilarial drug, in human urine by 1H-NMR spectroscopy.

1H-NMR spectroscopy is a convenient method for determination of diethylcarbamazine (DEC) in urine, and can be used to monitor medication with the drug. Urine samples were mixed with 10% of deuterium oxide as a spectrometer field frequency lock, which is the only sample pretreatment required. Tailored excitation with the 1331 pulse was used for water peak suppression. The quantification of DEC was carried out with the triplet of the N-ethyl group, for which the T1 relaxation time was 1 s. In aqueous solutions, amounts below 1 microgram ml-1 of DEC could be easily detected. In urine, the detectability depended on the level of chemical noise but was better than 10 micrograms ml-1. The accuracy and precision of the method were better than 15%. Analysis of urine from volunteers receiving a single therapeutic dose of DEC (6 mg kg-1 body weight orally) showed that the drug was eliminated in unchanged form during 2 days, in agreement with earlier results. The concentration of DEC in urine several hours after the intake exceeded 100 micrograms ml-1 making the 1H-NMR assay rapid and easy. No significant amounts of the N-oxide of DEC could be detected.

Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2. After s.c. administration of 14C and 13C P903, the Tmax in the blood was observed on day 2. Elimination was slow and > 95% was bound to protein. Radioactivity was distributed in the whole organism but particularly in erythrocytes and the lymphatic channel. Four days later, > 60% of the radioactivity was excreted in urine and faeces at equal amounts and 15% remained at the injection point. 3. In all biological fluids tested no P903 was found but only its metabolites. 4. One principal metabolite, the N-[(2-phenyloxo-2-ethane) sulphonyl] morpholine or oxosulphonamide was identified in blood, urine and faeces as compared with the reference compound by GC/MS and NMR. This latter molecule was detected following hydrolysis by hydrochloric acid but not with beta glucuronidase/sulphatase. 5. Unconjugated and conjugated oxosulphonamide represented > 85% of the radioactivity at all times tested in blood but only 38 and 35% respectively of urinary and faecal radioactivity on day 1 after the administration of the labelled drug. 6. Thus, P903 is rapidly converted to a reactive metabolite, probably an oxirene, which is then conjugated with endogenous components to form conjugated oxosulphonamide and an unknown metabolite. The role of this reactive metabolite in antifilarial activity seems to be very important in understanding the mechanism of action of P903.

Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100-1600 mg doses to patients with onchocerciasis.

The concentrations of CGP 6140 [4-nitro-4'-(N-methyl-piperazinylthiocarbonylamido)-diphenylamine] and of its N-oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100-1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half-life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25-40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3-4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax.

Effect of activated charcoal on diethylcarbamazine absorption in humans.

We investigated the effect of the oral binder-activated charcoal on the excretion of diethylcarbamazine. Six healthy volunteers were given 150 mg diethylcarbamazine with 350 mL water each. One and 2 weeks later, they received 150 mg diethylcarbamazine plus 7.5 and 15 g activated charcoal, respectively, in 350 mL water as a charcoal slurry. Urinary levels of diethylcarbamazine were measured spectrophotometrically from 1 to 72 hours after ingestion in three different periods. Treatment with activated charcoal led to 5.4% urinary recovery of diethylcarbamazine, decreased excretion rate, and a much lower plateau indicator of reduced absorption. Activated charcoal reduces the absorption and urinary excretion rate of diethylcarbamazine by adsorbing it in the gastrointestinal tract.