Fate of single oral doses of erythromycin acistrate, erythromycin stearate and pelleted erythromycin base analysed by mass-spectrometry in plasma of healthy human volunteers.

The kinetics of erythromycin acistrate (EA). a new ester prodrug of erythromycin, were studied in three comparative, randomized, cross-over studies in 29 healthy volunteers. A new mass-spectrometric method was used to assay separately erythromycin, 2'-acetyl erythromycin and their anhydro (spiroketal) forms. In Part I, the total antibiotic concentration was higher after EA than after erythromycin stearate (ES; 1.8-fold) and enterocoated pellets of erythromycin base (EB, enterocapsules; 1.4-fold). In plasma, however, only about one third of 2'-acetyl erythromycin was hydrolysed to active erythromycin. Moreover, after unprotected EA tablets, a considerable proportion of erythromycin and 2'-acetyl erythromycin was inactivated by gastric acid as reflected by high concentrations of respective anhydro (spiroketal) forms. In Part II, the unprotected (regular tablets) and acid-protected tablets (dissolution starts at pH 4.5) were compared. The protected tablet, albeit not an enterotablet, was not destroyed by gastric acid. Its absorption was slightly delayed but the bioavailability was good. In this study, the absorption of total antibiotic was 2.8-fold (unprotected tablet) and 3.9-fold (protected tablet) that after enterocapsules. In Part III, the bioavailabilities of 200 and 400 mg tablets (both acid-protected) were equal.

Absorption of erythromycin acistrate and erythromycin base in the fasting and non-fasting state.

Absorption of erythromycin acistrate (EA) and two erythromycin base (EB) preparations (enterotablet A and B) taken after an overnight fast or immediately before a standard breakfast was studied in 29 healthy volunteers in three separate studies, in a cross-over, randomized design. In Study I, the absorption of a single dose (400 mg) of EA was similar in the fasting and non-fasting state. There was, however, more interindividual variation and in two subjects absorption was markedly impaired in the presence of food. Cimetidine given at two doses (400 + 800 mg) had no effect on the pharmacokinetics of erythromycin acistrate. In Study II, the effect of food on the bioavailability of the two EB preparations was studied after a single dose of 500 mg (2 x 250 mg enterocoated tablets) and after multiple dosing (2 x 250 mg tid). When given with a standard breakfast, erythromycin base was significantly better absorbed from enterotablet A than from enterotablet B, whether given as a single dose or in repeated doses. Study III followed the same design as Study II except that the tablet size of both enterotablets A and B was now 500 mg. Even in this study the absorption of enterotablet A was significantly better than that of enterotablet B. EA is adequately absorbed when taken before a meal. Cimetidine does not interfere with its elimination. Concomitant food intake produced considerably dissimilar absorption of two commercially available enterocoated EB preparations. Although at steady-state this was less prominent than after a single dose, it may have some clinical significance.

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)

The fall of homovanillic acid and 5-hydroxyindoleacetic acid concentrations in brains of mice withdrawn from repeated morphine treatment and their restoration by acute morphine administration.

The striatal homovanillic acid (HVA) and cerebral 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were estimated in male mice withdrawn from 3- to 5-day morphine treatment (total dose: 1,100-2,350 mg/kg). All mice were given probenecid (200 mg/kg, 2 hours). The HVA concentration was decreased (by 26%) in mice withdrawn from 3-day treatment, but the 5-HIAA concentration fell (by 22%) only after 4-day treatment. An acute morphine dose (30 mg/kg, 2 hours) clearly elevated the HVA concentration in mice withdrawn from 4-day treatment, but mice withdrawn from 3-day treatment tended to be tolerant to the HVA concentration elevating effect of morphine. The acute dose increased the 5-HIAA concentration in mice withdrawn from 4-day treatment, by 20-40%, but the mice withdrawn from 3-day treatment were clearly tolerant to this effect of morphine. These results suggest that endogenous activities of dopaminergic and 5-HTergic neurons are attenuated by repeated morphine treatment. However, such attenuation seems to reactivate these neurons to respond to acute morphine administration nearly normally.

Pharmacokinetics of pipemidic acid in healthy middle-aged volunteers and elderly patients with renal insufficiency.

Pipemidic acid in bacteriological screening was more potent than nalidixinic acid, notably against Pseudomonas. In a study in middle-aged female volunteers, the relative bioavailability of a single 500 mg tablet of pipemidic acid was good. The main pharmacokinetic parameters were: tmax, 2.3 h; Cmax, 3.3 micrograms/ml; t1/2, 4.6 h; Varea, 2.04 l/kg; Cltot, 5.48 ml/min per kg; Clren, 3.05 ml/min per kg; Ae(0-24), 55.7% of dose. In elderly inpatients with normal renal function, the main alterations from middle-aged volunteers were: slightly elevated Cmax (+28%) and AUC (+13%) and significantly decreased Varea (-51%), Clren (-34%) and Ae(0-24) (-31%). In elderly inpatients with renal insufficiency, Clren (-58%) was decreased compared with elderly inpatients with normal renal function. Concn. of pipemidic acid in urine still exceeded several-fold the MIC values of the most pathogenic bacteria. Among all the subjects, there was a negative correlation between Clcreat and AUC0-infinity, and a positive correlation between Clcreat and Cltot, Clren and Ae(0-24). In the treatment of urinary-tract infections with pipemidic acid, a mild renal insufficiency (Clcreat 30 ml/min or more) does not necessitate dose adjustments.