Comparative study of coulometric and amperometric detection for the determination of macrolides in human urine using high-performance liquid chromatography.

A high-performance liquid chromatography (HPLC) method using chromatographic conditions optimised in a previous work was applied for the separation of three macrolide antibiotics roxithromycin (Rox), oleandomycin (Ole) and rosamicin (Ros) and further determination of two of them, roxithromycin (Rox) and oleandomycin (Ole), in human urine samples. A comparative study of the behaviour of these macrolides under the two types of electrochemical detection (EC) widely coupled with HPLC, that is coulometric (EC-C) and amperometric (EC-A), was carried out by applying the same multiresidue method. From the assays performed using both detectors the comparison was made taking relevant criteria such as detection limits, linearity, recovery and precision values into account. As a result of this comparison, the coulometric detector appears slightly more suitable than the amperometric one for macrolide analysis.

Cladinose analogues of sixteen-membered macrolide antibiotics. I. Synthesis of 4-O-alkyl-L-cladinose analogues via glycosylation.

The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as the neutral sugar are described. The nine novel derivatives have been synthesized by glycosylation with 1-thio sugars. The most active derivative of them showed prolonged antibacterial activity in rat plasma in vitro and improved pharmacokinetics.

Micro-method for the determination of roxithromycin in human plasma and urine by high-performance liquid chromatography using electrochemical detection.

A simple and sensitive high-performance liquid chromatographic micro-method for the determination of roxithromycin in human plasma and urine is described. A dichloromethane extract of the sample was chromatographed on a C18 reversed-phase column with acetonitrile-83 mM ammonium acetate-methanol (55:23:22, v/v) adjusted to pH 7.5 with acetic acid as the mobile phase. Roxithromycin and the internal standard, erythromycin, were detected by dual coulometric electrodes operated in the oxidative screen mode. The applied cell potential of the screen electrode was set at +0.7 V and the sample electrode at +0.9 V. The intra- and inter-assay coefficients of variation were less than or equal to 7.0%. The detection limit (signal-to-noise ratio = 3) was 0.1 microgram/ml for both plasma and urine. A study of drug stability during sample storage at 4, 20 and 37 degrees C showed no degradation of roxithromycin. The method is convenient for clinical monitoring and pharmacokinetic studies.

High-performance liquid chromatographic analysis of josamycin in serum and urine.

A high-performance liquid chromatographic assay for the analysis of josamycin in human serum and urine is presented. The assay involves a simple solid-phase extraction procedure coupled with a phase separation step, separation on a reversed-phase C18 column with UV detection by a multi-wavelength programmable detector. The mobile phase was acetonitrile-0.015 M phosphate buffer, pH 6.0 (5:2) at a flow-rate of 1.2 ml/min. The column temperature was maintained at 35 degrees C. Linear calibration curves over the concentration ranges 0.1-2.0 mg/l (serum) and 0.5-5 mg/l (urine) were obtained with correlation coefficients of 0.9983 and 1.0000, respectively. The relative standard deviations of five replicate samples at the upper and lower limits of each calibration curve were below 7%. The recoveries at the upper and lower ends of the calibration range for serum were 77% and 70%, respectively, and those for urine were 76% and 80%, respectively.

[Studies on the absorption and excretion of rokitamycin in infant beagle dogs. Comparison with adult beagle dogs].

Absorption and excretion of rokitamycin (RKM) were studied after oral administration of 50 mg/kg to fasted infant and adult Beagle dogs. In infant Beagle dogs, the mean plasma level of RKM reached its peak of 6.53 micrograms/ml in 15 minutes after administration. The area under the curve (AUC) value was 11.04 micrograms.hr/ml. In adult Beagle dogs, the mean plasma level of RKM reached its peak of 8.62 micrograms/ml in 30 minutes after administration. The AUC value was 18.25 micrograms.hr/ml. Ratios of Cmax and AUC value in infant Beagle dogs to those in adults were about 75% and 60%, respectively. In infant Beagle dogs, urinary excretion of RKM was 2.55% of the dose within 24 hours. In adult Beagle dogs, urinary excretion of RKM was 3.03% of the dose within the same period. The excretion ratio of RKM in infant Beagle dogs was about 85% of the adults' value.

[Studies on absorption and excretion of rokitamycin dry syrup in healthy volunteers].

The absorption and excretion of rokitamycin (RKM) in dry syrup form for children were studied following oral administration to fasted healthy volunteers with high gastric acidity as a suitable model to estimate bioavailability of RKM in children. In a comparative study on tablet and dry syrup forms, peak plasma concentrations of RKM and areas under plasma concentration-time curve (AUC) values were calculated using the trapezoidal rule. RKM dry syrup gave about 84 and 86% of these values for RKM tablet. Urinary recovery of RKM in 8 hours with the administration of dry syrup was also about 80% of the value obtained with tablet. Judging from these results, the bioavailability of RKM administered as dry syrup, was fairly close to that obtained with RKM tablet. The AUC values were dose dependent when examined with dose levels of 300, 500 and 800 mg administered as RKM dry syrup. The AUC value and urinary recovery of RKM administered as dry syrup were 3-4 times higher than these values for midecamycin acetate administered also as dry syrup.

[Studies of rokitamycin in pediatrics].

Pharmacokinetic, bacteriological and clinical studies on a new macrolide antibiotic, rokitamycin (RKM) dry syrup for pediatric use, were done, and results as summarized below were observed: 1. Five children with ages between 6 and 10 years were administered orally with RKM at a dose level of 10 mg/kg either at 30 minutes before or 30 minutes after meal on a crossover design, and plasma concentrations and urinary excretion rates of the drug were measured. Plasma concentrations of RKM following the administration before meal were 0.50 microgram/ml at 1/2 hour, 0.43 microgram/ml at 1 hour, 0.15 microgram/ml at 2 hours, 0.03 microgram/ml at 4 hours, and not detectable at 6 hours. Plasma concentrations following the administration after meal were 0.11 microgram/ml at 1/2 hour, 0.15 microgram/ml at 1 hour, 0.09 microgram/ml at 2 hours, 0.03 microgram/ml at 4 hours, and not detectable at 6 hours. The 0-6 hour urinary recovery rates were 1.41% following the administration before meal, and 0.93% following the administration after meal. These results suggested that the drug might be absorbed more rapidly, giving a higher plasma concentration, when administered before meal than when administered after meal. Changes in plasma concentrations of RKM following the administration of 10 mg/kg before meal were similar to those of two 100 mg RKM tablets (TMS-19-Q.GC tablets) to adult patients. Therefore, it seemed optimal to administer 10 mg/kg 3 times daily at fasting to children as a rule.(ABSTRACT TRUNCATED AT 250 WORDS)

Some pharmacokinetic data on miocamycin. I: Serum, urinary and prostatic levels.

The pharmacokinetics of miocamycin were studied in ten healthy male volunteers after three different administrations: the first group received 600 mg in a single oral dose; the second received 1200 mg divided into two administrations of 600 mg, each one every 12 h; the third received 1200 mg in a single oral dose. Prostatic levels of miocamycin were recorded after the administration of 1200 mg, divided into two administrations of 600 mg every 12 h. The pharmacokinetic analysis was carried out by applying a single-compartment kinetic model with zero-order absorption. The apparent duration of absorption (T) was about 0.55 h for all subjects. The area under the curve was 7.5767 +/- 0.2511 mg/h/l in the first group; 6.7333 +/- 0.6058 mg/h/l in the second group; and 18.6825 +/- 15.1555 mg/h/l in the third. The prostatic levels were five times higher than those in the serum at the same time.

[The pharmacokinetic studies on spiramycin and acetylspiramycin in rats].

Spiramycin (SPM) and acetylspiramycin (ASPM) have been known to be potent macrolide antibiotics in vivo, although spiramycins had rather mild antimicrobial activities in vitro. The physiological disposition of SPM and ASPM could participate in their in vivo activities. 14C-labeled SPM-I or 3H-labeled ASPM was administered intravenously in rats (20 mg/kg), and plasma levels, excretion and distribution have been studied. The plasma levels of SPM-I and ASPM were low both in radioactivity and bioactivity. After intravenous administration, 14C-SPM-I was excreted by 48 hours into urine, bile and faeces at the rates of 39.6, 31.4% and 37.1%, respectively. And 27.8% of the dose was recovered into urine by 48 hours after administration of 3H-ASPM. Higher radioactivities were detected in the spleen, kidney cortex, submaxillary gland, liver and lung by whole body autoradiography 1 hour after intravenous administration, and the levels tended to be retained until 24 hours. After intravenous administration at the dose rate of 50 mg/kg, the biological half-lives (T 1/2) of ASPM,SPM-I, josamycin and midecamycin were 151, 103, 71 minutes and 54 minutes, respectively, and the apparent volumes of distribution (V beta) were 9.2, 8.9, 3.6 L/kg and 7.7 L/kg, respectively. From these results, it was suggested that the highest activity observed for ASPM in experimental mice infections might be correlated with high affinity for the tissues and the long biological half-life of ASPM.

[A study on midecamycin granules in acute respiratory diseases in infants (author's transl)].

We have undertaken some basic and clinical studies on midecamycin granules with following results: 1) After ingesting of 4 g of midecamycin granules, peak blood levels (1.51 microgram/ml on an average) appeared at one hour in infants, detectable amount lasting for 6 hours. 2) Urinary excretion within 6 hours ranged from 1.1 to 2.7% of the drug dosed. 3) In the treatment of a total of 19 acute cases, consisting of 9 cases of tonsillitis, 7 cases of lacunar tonsillitis and 3 cases of bronchitis, midecamycin was found effective in 79% of the cases. 4) In all the 3 cases of pneumonia due to Mycoplasma, response to midecamycin was assessed as excellent. 5) Hepatic and renal functions tests performed in cases treated with the drug for a prolonged period (40 approximately 50 mg/kg for 13 approximately 18 days) revealed no undesirable effect, indicating that midecamycin can be administered continuously to younger infants with infections.

[Absorption, distribution and excretion of 14C-josamycin and 14C-josamycin propionate in rats (author's transl)].

Abosrption, distribution and excretion of 14C-josamycin (JM) and 14C-josamycin propionate (JM-P) were studied in rats by measuring both antibacterial activity and radioactivity. 1. In antibacterial activity, plasma and tissue concentrations of JM-P showed a similar tendency to those of JM. Those concentrations of JM reached a peak at 1 hour after administration with a subsequent rapid decrease, while the peak level of JM-P appeared 2 approximately 4 hours after administration and then fell down very slowly. 2. In radioactivity, oral administration of JM-P rapidly produced a very high plasma and tissue concentrations which were in lung, liver, kidney and spleen more than twice those of JM. These results showed that when given orally, JM-P is well absorbed with distributions at high concentrations especially in lung, liver, and kidney and spleen. 3. The ratios of bioactivity/radioactivity in JM administration were the highest in lung and the lowest in liver at 1 hour after. But those of JM-P were generally much lower than those of JM because of higher distribution of JM-P radioactivity into tissues. 4. Four days after oral administration of JM and JM-P, 23.1% and 21.8% of the given radioactivity were recovered respectively from urine. However, the antibacterial activities recovered were 0.40% for JM and 0.65% for JM-P. 5. Biliary recoveries of JM and JM-P were 17.2% and 12.1% of administered radioactivity 2 days after oral administration. On the other hand, 0.47% of JM and 0.17% of JM-P were excreted into bile as antibacterial activity. These results showed that JM and JM-P were excreted into rat urine and bile as some metabolites with less biological activity. 6. The amounts of JM and JM-P recovered from feces were 75.7% and 60.2%, respectively, of the orally given radioactivity. The amount of radioactivity recovered from expiration air was about 1% of either orally given JM or JM-P.