Effect of food on absorption and hydrolysis of erythromycin acistrate.

Effect of food on absorption of erythromycin acistrate (2'-acetyl erythromycin stearate, Erasis; CAS 96128-89-1) was studied in 14 healthy volunteers in a randomized cross-over design. The subjects were given 400 mg erythromycin acistrate enteric coated tablets b.i.d. for 4 days. On the 1st and 4th days the tablets were taken after an overnight fast or immediately after a light or a heavy breakfast. Erythromycin (E), 2'-acetyl-erythromycin (2AE), anhydroerythromycin and anhydro-2'-acetyl-erythromycin concentrations in plasma were analyzed chemically by HPLC. After a single dose the lag time of absorption (tlag) was significantly longer after both types of breakfasts as compared to fast. The tmax of E and 2AE were also somewhat delayed by food although tmax of 2AE after a heavy breakfast only differed statistically significantly from that of the fasting state. Food significantly delayed the absorption especially in some subjects since no drug was observed during the 12-h observation period in 2 and 5 of the subjects after a light and heavy breakfast, respectively. At steady state the delaying effect of food on absorption had almost disappeared. No significant differences were observed in Cmax- or AUC0-12-values between the fasting and the fed states both after a single dose or at steady state. It is concluded, that food does not affect the mean bioavailability of erythromycin acistrate neither the mean rate of absorption but in some subjects the absorption from enteric coated tablets might be significantly delayed.

Antibiotic concentration in suction skin blister fluid and saliva after repeated dosage of erythromycin acistrate and erythromycin base.

The drug concentration in plasma, suction skin blister fluid (SBF), urine and saliva after repeated dosage of either erythromycin acistrate (EA) or enterocoated pellets of erythromycin base (EB) was studied in young healthy volunteers with a cross-over design in two separate studies. In Study I, the total drug concentration (erythromycin + 2'-acetyl erythromycin) after EA (400 mg tid) was slightly higher than the erythromycin concentration after EB (500 mg tid). The concentration of erythromycin after EA was about half of that after EB. In SBF the total antibiotic concentration after EA and erythromycin concentration after EB were 49 and 46% of the corresponding plasma concentrations, respectively. The degree of hydrolysis of 2'-acetyl erythromycin was higher in SBF (44%) than in plasma (39%). An equal proportion (7.3-7.5%) of the dose was excreted in urine after administration of both drugs. The degree of hydrolysis of 2'-acetyl erythromycin in urine was 58%. In Study II, the plasma/saliva concentration ratio ranged from 0.11 to 0.17 after EA 400 mg tid, 0.12 to 0.20 after EA 500 mg tid and 0.17 to 0.22 after EB 500 mg tid. The degree of hydrolysis of 2'-acetyl erythromycin was considerably higher in saliva (61-78%) than in plasma (27-41%). In plasma, the percentage of hydrolysis of 2'-acetyl erythromycin was inversely correlated with the concentration of acid-alpha 1-glycoprotein. The penetration of 2'-acetyl erythromycin and erythromycin into the extravascular space as evaluated from SBF and saliva levels was equal, and adequate concentrations of erythromycin were obtained for the treatment of bacterial infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of 2'-acetyl erythromycin and erythromycin in human tonsil tissue by HPLC with coulometric detection.

A simple and sensitive high-performance liquid chromatographic method was developed for the determination of 2'-acetyl erythromycin and erythromycin in human tonsil tissue. Methyl tert-butyl ether was used as the extraction solvent after alkalization of tissue homogenates. Separation was achieved on a reverse phase C-18 column. The mobile phase consisted of acetonitrile-methanol-tetrahydrofuran-sodium acetate buffer, pH 4.5. Eluted compounds were monitored by a coulometric detector in the oxidative screen mode. The quantitation limits of 2'-acetyl erythromycin and erythromycin were 0.20 and 0.30 mg/kg of tissue, respectively. The method was linear over the concentration range of 0.60-10.0 mg/kg of tissue for 2'-acetyl erythromycin and erythromycin.

Tonsillar penetration of erythromycin and its 2'-acetyl ester in patients with chronic tonsillitis.

Concentrations of erythromycin and 2'-acetyl erythromycin were analysed in serum or plasma and tonsil tissue after repeated dosage of erythromycin acistrate (EA), a new erythromycin prodrug, in two separate studies in 61 young patients. The reference preparations were: (1) enterocoated tablets of erythromycin base (EB enterotablets, (2) erythromycin base as enterocoated pellets (EB enterocapsules) and (3) erythromycin stearate (ES). All drugs were given 500 mg tid for three days before scheduled tonsillectomy. Tonsils were removed about 3 h after intake of the last dose. Blood samples were collected at 0, 2 and 6 h and at the time of tonsillectomy. At all time points EA produced several-fold higher total drug (erythromycin + 2'-acetyl erythromycin) concentrations in serum or plasma than any of the reference preparations. Similarly, after EA the mean total antibiotic levels in tonsil tissue exceeded the erythromycin levels after the reference preparations by at least a factor of 3. Tonsil/serum or plasma ratios of the total antibiotic were quite similar with all preparations (means 38-50%). Peak erythromycin levels in circulation did not differ significantly from each other in spite of two nonabsorbers after EB enterotablets. The same was true of tonsil tissue. There were, however, 15 tonsils with undetectable erythromycin: 4/25 (16%) with EA, 5/12 (42%) with EB enterotablets, 2/12 (17%) with EB enterocapsules and 4/12 (33%) with ES. The degree of hydrolysis of 2'-acetyl erythromycin to erythromycin was 23-43% higher in tonsil tissue than in circulation.

Effect of enzyme induction and inhibition on the fate of metronidazole and tinidazole in the rat.

The excretion routes of intact metronidazole and tinidazole were studied in rats kept in metabolism cages and cannulated for continuous bile collection. The nitroimidazoles were given intraarterially either alone or after a 5-day pretreatment with phenobarbitone (70 mg/kg/day intravenously) or after a single dose of cimetidine (50 mg/kg intraarterially). After 30 mg/kg, 27.0% of the metronidazole dose was excreted intact in 24-hr urine and 2.2% in bile. After tinidazole, the recoveries of the intact drug in urine and bile were 48.1% and 1.7%, respectively. After 90 mg/kg, the total recoveries of both drugs were 25-28% smaller than after 30 mg/kg. Phenobarbitone pretreatment did not affect metronidazole levels in plasma but decreased tinidazole levels at 4 hrs. The 24-hr recoveries of the intact nitroimidazoles in urine were significantly reduced by phenobarbitone while the 24-hr bile recoveries were not. Cimetidine treatment enhanced both metronidazole (at 1, 2 and 3 hrs) and tinidazole (only at 1 hr) concentrations in plasma, but this shift was not reflected in the 24-hr urine recoveries of the intact nitroimidazoles. Cimetidine doubled, however, the 24-hr bile recovery of the intact tinidazole. The calculations of the apparent degree of metabolism, assuming no methodological losses, showed that phenobarbitone increased the metabolism of tinidazole by about 62% and that of metronidazole only by about 16%. The effect of a single dose of cimetidine was negligible.

Continuous infusion of fentanyl or alfentanil for coronary artery surgery. Plasma opiate concentrations, haemodynamics and postoperative course.

Nine patients received a mean total dose of 110 micrograms kg-1 of fentanyl and 10 patients received alfentanil 1379 micrograms kg-1 as a continuous infusion during coronary artery bypass grafting (CABG). Circulatory stability was well maintained through the induction of anaesthesia and a similar cardiovascular course was achieved with both agents, with the exception of small differences in heart rate and cardiac index immediately before tracheal intubation. Similar haemodynamic responses to sternotomy, cardiopulmonary bypass and awakening from anaesthesia were found with both analgesics. Although the times to awakening and extubation were somewhat shorter in patients receiving alfentanil, the differences between the groups were not significant. With the continuous infusion techniques, plasma opiate concentrations could be maintained well above the awakening values during cardiopulmonary bypass. In a total dose ratio of 1:13, fentanyl and alfentanil produced similar haemodynamic profiles and clinical courses in patients undergoing CABG.

Pharmacokinetics of slow-release diltiazem and its effect on atrioventricular conduction in healthy volunteers.

The pharmacokinetics and effect of a slow-release and a conventional diltiazem tablet on atrioventricular conduction were compared in a randomized cross-over study after a single dose and at steady state in 12 healthy volunteers. The time to peak concentration was significantly delayed after the slow-release as compared to the conventional tablet, both after a single dose (2.7 vs. 0.9 h) and at steady-state (1.9 vs. 0.9 h). The peak concentration was also significantly reduced. There was no marked loss in bioavailability with the slow-release formulation. The maximal fluctuations in serum diltiazem at steady-state for the slow-release tablet were markedly less than after the conventional tablet (62 vs 87%). The PQ-interval was longer after the conventional tablet as compared to the slow-release tablet (both in doses of 120 mg) after a single dose (187 vs 163 ms) and at steady-state (197 vs 174 ms). The maximal prolongation was seen 1 h after intake of the drug. Heart rate was decreased only by 6-9 beats/min, irrespective of the dose. Slow-release diltiazem appears to have many advantages over a conventional tablet.

Concentrations of metronidazole and tinidazole in male genital tissues.

The steady-state concentrations of metronidazole and tinidazole in male genital tissues were analyzed in patients subjected to elective gonadal surgery. The nitroimidazoles were administered orally at 500 mg every 8 h, beginning 5 days before the operation. Eight hours after the last dose, the concentrations of tinidazole were 24.1 +/- 2.5 micrograms (mean +/- standard error of the mean)/g of prostatic tissue, 29.1 +/- 2.9 micrograms/g of vas deferens, 22.1 +/- 2.1 micrograms/g of epididymis, and 18.6 +/- 2.3 micrograms/g of testis. The corresponding values of metronidazole were 14.3 +/- 1.8 micrograms/g, 15.9 +/- 1.2 micrograms/g, 14.0 +/- 1.2 micrograms/g, and 12.5 +/- 1.7 micrograms/g, respectively.

Concentrations of metronidazole and tinidazole in female reproductive organs after a single intravenous infusion and after repeated oral administration.

Concentrations of metronidazole and tinidazole in serum and gynecological organs were analyzed after a single 500 mg intravenous infusion and after three days of treatment with 400 mg t.i.d. of metronidazole or 500 mg b.i.d. of tinidazole. The studies were performed in 67 patients subjected to hysterectomy and/or oophorectomy because of myomatosis uteri, carcinoma uteri or endometriosis. At the time of organ removal (about 30 min after infusion), metronidazole and tinidazole levels in serum were 14.5 +/- 0.45 mg/l and 12.3 +/- 0.38 mg/l, respectively. Concentrations of both drugs in the uterus and Fallopian tube were about the same as the simultaneous serum levels and concentrations in the ovaries about 55% thereof. At steady-state, the concentrations of tinidazole in serum (23.5 +/- 1.0 mg/l) were remarkably higher than those of metronidazole (13.5 +/- 0.84 mg/l) about three hours after the last oral dose. Drug concentrations in organs of the female reproductive tract were 70 to 100% those of the simultaneous serum levels.

A simple procedure using 4-methylpyrazole for developing tolerance and other chronic alcohol effects.

Young rats given ethanol chronically by gradually increasing the concentration in the drinking fluid to 17.5% reached a maximal daily consumption of 15-17 g ethanol/kg body wt., which corresponded to 35-40% of their energy intake. This chronic treatment was markedly potentiated by additional supplementation of the drinking fluid with a low dose of the alcohol dehydrogenase inhibitor 4-methylpyrazole. Rats on this regimen exhibited higher and more sustained blood ethanol levels. Consequently, more pronounced functional and metabolic tolerance developed and more frequent signs of physical dependence was observed than in rats drinking only ethanol solution. Simple provision of drinking fluid supplemented with ethanol and 4-methylpyrazole appears to provide a nutritionally adequate and easy way to produce tolerance and other chronic alcohol effects.

Concentrations of metronidazole and tinidazole in abdominal tissues after a single intravenous infusion and repetitive oral administration.

Concentrations of metronidazole and tinidazole in serum and abdominal tissues were determined after a single 500-mg intravenous infusion or after a 5-day oral dosage of 500 mg three times daily in groups of 10 patients each. In the patients who got the single infusions, the concentrations in tissues (except fat) reached almost the serum levels 10 min after the infusion. At 24 h, the tinidazole concentrations in serum averaged 3.2 micrograms/ml and those of metronidazole 1.3 micrograms/ml. In the patients who got the 5-day oral dosages, the steady-state levels of tinidazole in both serum and tissues were twice as high as those of metronidazole.